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Human diseases caused by protozoan parasites are renowned for their high rates of morbidity and mortality worldwide. Some examples include African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease, leishmaniases, malaria and babesiosis. These infections tend to follow a chronic rather than an acute course with lifelong persistence of parasites. Regulatory T cells (Treg), in particular the CD4 + CD25 + cell subset, appear to control the immune competence of host response triggered by the presence of parasites, promoting homeostasis and protecting the host from collateral tissue damage whilst allowing parasite persistence. To date, there is still considerable controversy on the characteristics and function of these cells when induced during different protozoan infections, evidencing the need of further research. Therefore, this review aims to provide a comprehensive overview about Treg cells development, phenotype determination and general functions. The above pathologies were used as selected examples to discuss the role of Treg cells during protozoan infections. Understanding of the mechanisms that contribute towards homeostasis and the survival of the host, and simultaneously allow the persistence of the pathogen, may yield important insights for new strategies of prophylaxis and therapy.
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
Abstract Human diseases caused by protozoan
parasites are renowned for their high rates of morbidity
and mortality worldwide. Some examples include African
trypanosomiasis or sleeping sickness, American
trypanosomiasis or Chagas disease, leishmaniases,
malaria and babesiosis. These infections tend to follow a
chronic rather than an acute course with lifelong
persistence of parasites. Regulatory T cells (Treg), in
particular the CD4+CD25+ cell subset, appear to control
the immune competence of host response triggered by the
presence of parasites, promoting homeostasis and
protecting the host from collateral tissue damage whilst
allowing parasite persistence. To date, there is still
considerable controversy on the characteristics and
function of these cells when induced during different
protozoan infections, evidencing the need of further
research. Therefore, this review aims to provide a
comprehensive overview about Treg cells development,
phenotype determination and general functions. The
above pathologies were used as selected examples to
discuss the role of Treg cells during protozoan infections.
Understanding of the mechanisms that contribute
towards homeostasis and the survival of the host, and
simultaneously allow the persistence of the pathogen,
may yield important insights for new strategies of
prophylaxis and therapy.
Keywords Protozoan infections; Regulatory T cells;
CD4+CD25+FoxP3+ T cell subset; Trypanosoma spp.;
Leishmania spp.; Plasmodium spp.; Babesia spp.
Submitted and accepted Jan 2015.
1Global Health and Tropical Medicine, Instituto de Higiene e Medicina
Tropical, Universidade Nova de Lisboa, Rua da Junqueira 100, 1349-008
Lisboa, Portugal.
*Correspondence to G. Santos-Gomes (e-mail:
ROTOZOAN parasites are the causative agents of many
insect-borne infections that continue to represent major
threats to human health worldwide [1]. In developing
countries, these diseases constitute an important cause of
morbidity and mortality [2, 3], mainly due to the limited
availability of therapies and lack of affordable and effective
vaccination strategies [4, 5]. Some examples include African
trypanosomiasis or sleeping sickness, American
trypanosomiasis or Chagas disease, leishmaniasis, malaria
and babesiosis, which are caused by Trypanosoma brucei,
Trypanosoma cruzi, Leishmania spp., Plasmodium spp., and
Babesia spp., respectively.
In immunocompetent individuals, despite the existence of
a strong anti-protozoan response, the immune system seems
to allow the persistence of a small number of parasites, with
parasite load persisting for a long time at a tolerable level.
Thus, the infections tend to follow a chronic rather than an
acute course [6], as sterile immunity is difficult to achieve,
which could be beneficial for the host in endemic areas,
leading to the establishment of protective cell memory [7]. In
addition, since these parasites are able to establish a
persistent infection, situations that disturb the immune
system, such as malnutrition, advanced age or co-infections
can lead to the reactivation of these infections. More recently,
an emergent problem has arisen in humans regarding
acquired immunodeficiency, caused for example by Human
Immunodeficiency Virus (HIV) or by specific immune
suppressor treatments, responsible for an increase of immune
compromised individuals. In these individuals the normally
asymptomatic or latent protozoan infections can be triggered
and cause significant clinical disease (reviewed by Mendez et
al. [8]).
Over recent years, the concept of a self-regulating immune
system has been researched extensively. The potency of the
host immune response triggered by the presence of parasites
has to be strongly counterbalanced by regulatory responses
that control the extent of auto-reactive responses and promote
homeostasis during infection. It is therefore important to
achieve effective parasite control whilst protecting the host
from tissue damage, preventing clearance of infection [6, 9,
10]. If uncontrolled by the regulatory mechanisms, the
induction of a strong immune response can cause
immunopathology and even lethality [9]. Amongst others,
one such mechanism involves the generation of
immunosuppressive regulatory T cells (Treg) [11]. Under
The Role of Regulatory CD4+CD25+ T Cell Subset in Host Homeostasis
during Protozoan Infection: An Overview
J. Ferrolho1 DVM, MScVetSc, MScRes, N. Domingues1 BSc, MSc, A. Domingos1 BSc, MSc, PhD,
Santos-Gomes, G1* BSc, PhD
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normal conditions, Treg cells can regulate the innate and
adaptive immune responses and control the excessive and
misdirected response mediated by effector T cells [12, 13].
This study aims to review the published information about
the induction and the role of Treg cells, in particular the
CD4+CD25+ Treg cell subset, in maintaining homeostasis
during the immune response triggered by the presence of
protozoan parasites responsible for trypanosomiasis,
leishmaniasis, malaria and lastly babesiosis. In order to
understand how the regulatory mechanisms exert their action,
a brief overview describing the development of Treg cells,
phenotype determination and general functions is provided.
Finally, an understanding of the mechanisms by which
regulation of the immune system ensures homeostasis and
avoids severe immunopathology of the host by suppressing
immune response, and simultaneously allows persistence of
the pathogen, may yield important evidences to incorporate
into the design and development of novel strategies for
prophylaxis and therapeutics.
A. Regulation of the immune system: Regulatory T cells
A large and ever increasing body of data is accumulating
on a specialized subset of Treg cells, the CD4+CD25+ T cells,
also known as natural or endogenous regulatory T cells
(nTreg). In healthy humans, these cells comprise 2-4% of
peripheral CD4+ T cells, whereas in mice represent 5 to 10%
[14]. This subset of cells is able to prevent autoimmunity
through inhibition of the activation and expansion of
autoreactive T cells and actively maintain peripheral
tolerance [12, 15, 16]. Treg cells are able to recognize
self-antigens in autoimmunity, as well as exogenous antigens
in hypersensitivity and infectious diseases [17, 18].
B. Development of regulatory T cells
Uncommitted thymocytes differentiate into either a CD4+
or a CD8+ thymocyte. Within the thymus, nTreg cells
develop from naïve CD4+ thymocytes following exposure to
antigen and self-stimulation with cytokines [19]. This yields
a fully functional mature subset of T cells which migrate to
the periphery and are immediately able to suppress
auto-reactive conventional T cells. nTreg cells exhibit a
characteristic immune phenotype which include the
expression of the transcription factor forkhead box P3
(FoxP3) [20] and of the surface markers cytotoxic
T-lymphocyte antigen 4 (CTLA-4), CD28,
glucocorticoid-induced TNF receptor-related protein (GITR)
and the interleukin (IL)-2 receptor α (CD25) [21]. In addition
to thymically derived Treg cells, naïve lymphocytes (both
CD4+ and CD8+) move to peripheral sites and undergo
maturation to produce further distinct subsets. Naïve CD8+ T
cells develop into a minor Treg population, which may or
may not express FoxP3, following exposure to foreign or
self-antigen [22]. By contrast, the naïve CD4+ cells that have
migrated are induced through exposure to a low dose of
antigen alongside stimulation with the cytokines IL-2 and
transforming growth factor (TGF)-β [23, 24]. These cells
commonly referred to as “induced” Treg cells (iTreg) express
FoxP3 and maintain peripheral tolerance [24].
Mucosa-associated lymphoid tissues (MALT) are further
sites where the development and expansion of distinct
subsets of Treg cells can be driven by cytokines.
MALT-resident antigen presenting cells (APC) secrete
IL-10, TGF-β or a “cocktail” of IL-2/TGF-β/retinoic acid,
which, respectively, leads to the differentiation of naïve
CD4+ T cells into regulatory T cells of type 1 (TR1) [25], T
helper 3 cells (Th3) [26] and iTreg cells [27]. When exposed
to the altered microenvironment created under certain
pathological conditions, Treg cells can lose FoxP3
expression and consequently, their ability to suppress other
cells, behaving like conventional effector T cells. All these
potential outcomes generate an enormous plasticity within
the peripheral pool of T cells [28]. In addition, the in vitro
stimulation of Treg cells with IL-6 causes the loss of FoxP3
and differentiation into T helper 17 cells (Th17) that secrete
IL-17 [29].
C. Function of Regulatory T cells
The major function of Treg cells is to maintain immune
cell homeostasis. This is achieved via four alternative
mechanisms that negatively regulate conventional T cells and
dendritic cells (DC), although other major groups of immune
cells such as natural killer (NK) cells can also be inhibited.
One such mechanism involves the use of suppressive
cytokines or other molecules, which are either secreted or
expressed on the surface of Treg cells. Contact-dependent
inhibition of CD4+ or CD8+ effector T cells is achieved
through exposure to TGF-β attached to the Treg cell
membrane [1]. Treg cells can also secrete IL-10, IL-35 or
TGF-β, which induce cell cycle arrest in effector T cells
located nearby [2]. The secretion of IL-10 can also block
co-stimulation of DC. Furthermore, galectin-1 can be
released by Treg cells to induce apoptosis in adjacent T cells
expressing the CD45 and CD43 glycoprotein receptors.
A second mechanism adopted by CD8+ Treg cells also
induces apoptosis in either T cells or DC. The secretion of
perforin molecules creates pores in the membranes of
effector T cells or DCs and granzymes (A or B) giving origin
to the cascade of caspases, ending in programmed cell death
(reviewed by Sakaguchi et al. [2]).
A third mechanism of Treg-mediated suppression involves
disrupting the metabolic function of target cells. There are
three well-defined ways by which this is achieved. Firstly,
Treg cells are capable of depriving conventional T cells of a
source of IL-2, attenuating their proliferation, [32] leading to
apoptosis. Secondly, Treg cells can initiate indirect apoptosis
of T cells via a DC intermediate. In this situation, CTLA-4
expressed on the surface of Treg cells binds to either CD80 or
CD86 molecules found on DC, upregulating indoleamine
2,3-dioxygenase production in DC [3]. This enzyme
catabolises tryptophan and the simultaneous depletion of this
essential amino acid starve nearby T cells, directing them to
apoptose. Finally, the CD39 and CD73 glycoproteins on the
surface of Treg cells synthesize adenosine from adenosine
triphosphate in the extracellular space [4]. Both DC and
conventional activated T helper cells express the adenosine
receptor A2AR, and following binding of the nucleoside, are
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inhibited. In the case of DCs, their maturation and ability to
stimulate T cells is suppressed. Helper T cells are suppressed
by adenosine through its effect on their production of
cytokines. A significant reduction in the secretion of IL-2,
IL-4, tumor necrosis factor (TNF)-α and interferon gamma
(IFN)-γ is observed due to decreased transcript stability in
these cells [4].
A fourth mechanism of FoxP3+Treg cells mediated
suppression consists of alternative ways to target DC, of
which three different contact-dependent mechanisms have
been defined. Firstly, FoxP3+ Treg cells use their T-cell
receptors to engage class II molecules of major
histocompatibility complex (MHCII) on the surface of DC.
Coupled with the binding of Neuropilin-1 on the Treg cell
surface to its similar receptor found in DC, prolongs their
interaction at the immunological synapse, outcompeting
nearby T helper cells and causing the suppression of APC [5].
A second way implies targeting of DC and inhibition of cell
maturation. Here, the lymphocyte activation gene 3
transmembrane protein expressed by FoxP3+ Treg cells binds
to MHCII on the surface of DC, inhibiting their activation
[6]. The third alternative DC-targeting mechanism employed
by iTreg cells uses the CTLA-4 receptor present in
membrane. This constitutively expressed protein binds to
CD80/CD86 molecules on the DC surface which leads to
their internalization in a process termed trans-endocytosis [7]
inhibiting DC function.
D. Regulatory T cells preventing autoimmunity
Treg cells have been identified as the key players in a
number of important immune responses in vivo. One such
example is the prevention of autoimmunity whereby Treg
cells suppress the activation of the effector T cells. In mice
depleted of Treg cells, autoimmunity prevails, however, the
reconstitution of this CD4+CD25+ T cell subset prevents
autoimmunity [8]. Nonetheless, more recent evidence has
indicated that effector T cells are able to resist this
suppression. For example, in patients with rheumatoid
arthritis [9] and multiple sclerosis [10], Treg-mediated
suppression is lost and peripheral blood Treg cell counts are
similar between patients and healthy controls. A recent study
has deciphered the underlying mechanism responsible for
this absence of regulation. In patients with juvenile idiopathic
arthritis, resistance to Treg suppression is mediated by
hyperactivation of protein kinase B in effector T cells at the
site of inflammation [11]. This is a direct consequence of
these cells being stimulated by IL-6 and TNF-α, though other
cytokines and CD28 signaling may also contribute [11].
E. Regulatory T cells promoting chronic infection
Another important manifestation influenced by
CD4+CD25+FoxP3+ Treg cells is the establishment of chronic
infection. A broad spectrum of pathogens, including bacteria
(Helicobacter pylori), fungi (Candida albicans), protozoan
(Leishmania major) and virus (hepatitis C virus) has been
shown to become manifested as persistent human infections
because the action of Treg cells [12].
Most protozoan infections follow a chronic rather than an
acute course, with the parasite persisting for a long time [13,
14]. To achieve effective parasite control, whilst protecting
the host from tissue damage, a fine balance needs to be
achieved by Treg cells to limit the potency of the host
immune response. An overabundance of Treg cells or their
overactivation may cause immunopathology and lethality
and, also allow pathogens to become transmitted more easily
[15]. Somewhere between these two extremes exists a
balance between the immunosuppressive activity of Treg
cells and effector T cells. Although the host may benefit from
milder pathology and be protected from disease, this can be
where infections persist and become established as chronic
diseases [12].
Despite the complex interactions between parasites and
their hosts, considerable progress has been made to
understand the involvement of Treg cells during many
protozoan infections. Though their role is not very well
defined, some illustrative examples of protozoan infections
that involve Treg cells in their pathogenesis are reviewed.
A. Leishmaniasis
Leishmaniasis, caused by Leishmania spp., is a serious
public health issue with a worldwide distribution [16].
Leishmania includes a broad genus of obligatory intracellular
flagellate protozoa that infect mononuclear phagocytes [17].
Leishmania uses a very distinct strategy to preserve their
life cycle based on just two morphological forms: the
amastigote, a non-flagellated form that resides intracellularly
within the mononuclear cells of their mammalian hosts, such
as humans, dogs and rodents, among others; and the
promastigote, an extracellular flagellate form that develops in
the intestinal tract of sandfly. The vector, a female sandfly of
the genus Phlebotomus and Lutzomyia ingests amastigote
forms while feeding on the mammal host and, within the
midgut, the amastigote forms develop into infective procyclic
promastigote forms [18]. In a subsequent blood meal, the
female sandfly deposits the promastigote forms into a
mammalian host [19]. Shortly after inoculation, these
promastigote forms are phagocyted by dermal macrophages
and/or DC at the site of the bite and, inside phagolysosomes,
they transform into amastigotes and replicate [17, 19]. The
excess of parasite load inside the cells due to parasite
replication within the phagolysosome leads to cell lysis and
the free amastigotes will then infect new phagocytes. The life
cycle is completed when the female sandflies ingest infected
phagocytes [18].
Leishmania spp. are responsible for a wide variety of
disease presentations, namely the polymorphic cutaneous
forms, the rare mucocutaneous and the fatal disseminated
visceral form [17]. Clinical symptoms are caused by parasite
dispersion within macrophages by nasopharyngeal mucosa
and by organs of the mononuclear phagocytic system
(reviewed by Campanelli et al. [20]).
Cutaneous leishmaniasis can be caused by L. major, L.
tropica and L. aethiopica in Africa, Middle East and parts of
Asia [17], and by several Leishmania species of the
braziliensis and mexicana complexes in central and South
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America. In most vertebrate hosts, the infection is
characterized by a period of latency, followed by lesion
development that may not ulcerate [15].
During infections caused by Leishmania spp., in particular
cutaneous leishmaniasis, regulation of the immune response
is important for two reasons: firstly, it allows the persistence
of the parasite within the host cells after clinical resolution;
and secondly, contributes to the establishment of the host cell
memory [21], and eventually protection against re-infection.
After successful chemotherapy or self-cure, low numbers of
viable parasites will persist within lymphoid tissue and at the
skin lesions, giving rise to latent infections [22, 23].
Macrophages and DCs were found to harbor persistent
parasites within the lymph nodes [24, 25]. This latent
infection can be reactivated as a result of
immunosuppression, environmental factors or with advanced
age (reviewed by Mendez et al. [23]) and give rise to visceral
leishmaniasis and mucosal leishmaniasis (reviewed by
Belkaid et al. [22]). The equilibrium established during
chronic infection might reflect both parasite and host survival
strategies. From the host point of view, the inability to
achieve an absolute cure is beneficial, especially if they
reside in endemic areas, where an efficient memory response
is important [21, 26].
Different studies support the fact that Treg cells, in
particular the CD4+CD25+ subset, have a fundamental role
controlling the outcome of Leishmania infection, among
various immune mechanisms. A study determined that
CD4+CD25+ Treg cells are essential for the development and
maintenance of a persistent cutaneous infection with L. major
in resistant C57BL/6 mice. Treg cells rapidly accumulated at
primary sites of infection, suppressing the capacity of the
immune response to completely eliminate the parasite [26].
In humans with cutaneous leishmaniasis, CD4+CD25+ Treg
cells were found in chronic skin lesions caused by L.
braziliensis [20].
Treg cells can also control the intensity of the memory
response and the balance between these cell subset and
effector T cells seems to affect the course of the disease.
Mendez et al. [23] found that during memory responses, the
number of CD4+CD25+ Treg cells increased at sites where the
infection was reactivated. Similarly, the presence of Treg
cells during human L. major infection was confirmed to be
higher in chronic lesions in comparison to effector T cells,
which in turn were more frequent in active lesions [27].
Overall, results show that the balance between Treg and
effector T cells determines the outcome of infection. The
balance tendency towards Treg cells in chronic infections and
their presence at the time of memory response might be the
cause of long-lasting disease and a decisive factor governing
the efficiency of effector immune responses.
CD4+CD25+ Treg cells produce the immunosuppressive
cytokine IL-10 that is now known to play a role in parasite
persistence. Belkaid et al. [22] investigated the factors that
control L. major persistence and reactivation after clinical
cure. Comparing acute and chronic infections in C57BL/6
and C57BL/10 wild-type mice and in IL-10 knockout mice,
they have found that IL-10 is required for L. major
persistence. During the chronic stage, IL-10 deficient mice
and wild-type mice treated with anti-IL-10 antibody achieved
sterile immunity, with complete clearance of parasites from
the skin. Kane and Mosser [28] confirmed the role of IL-10 in
cutaneous leishmaniasis. After L. major infection, it was
shown that genetically susceptible BALB/c mice lacking
IL-10 were able to control disease progression, developing
relatively small lesions; however, BALB/c wild-type mice
developed progressive non-healing lesions with numerous
parasites [28]. More recently, the production of IL-10 by
CD4+CD25+ Treg cells was confirmed in C57BL/6 mice
infected with a strain of L. major responsible for non-healing
dermal lesions [29]. The results support the fact that IL-10
exerts a potent inhibitory effect on macrophage activation,
especially at the level of cytokine production [30] and
leishmanicide capability [31, 32].
Treg cells can downregulate both protective T helper (Th)
1 and pathogenic Th2 responses and the balance of Th1 and
Th2 cell functions is critical for the outcome of cutaneous
leishmaniasis. Belkaid et al. [26] have shown that in
genetically resistant mice, CD4+CD25+ Treg cells suppress
Th1 cells, preventing the parasites from being completely
eliminated whilst in susceptible mice, Treg cells prevent the
early appearance of lesions and lead to a better control of
parasites in the long term. CD4+CD25+ Treg cells can also
suppress the differentiation of Th2 cells and prevent the
development of progressive lesions caused by L. major in
susceptible mice [33]. In addition, after L. major infection,
BALB/c mice depleted of CD4+CD25+ Treg cells, in
comparison with wild-type BALB/c mice, develop more
severe lesions with higher numbers of parasites, probably
because CD4+CD25+ Treg cells downregulate IL-4 secretion
by CD4+ T cells, thus affecting Th2 cell maturation [34].
Visceral leishmaniasis, commonly known as Kala-azar, is
caused by L. donovani in South Asia and Africa and by L.
infantum in the Mediterranean region, the Middle East, Latin
America and some areas of Asia [17]. Parasite replication
within macrophages with further spreading to other locations
of the mononuclear phagocytic system is responsible for
disease pathogenesis [16].
During murine leishmaniasis, CD4+CD25+ Treg cells also
seem to play a role during the course of L. infantum infection,
promoting parasite persistence and the establishment of
chronic infection. After experimental infection of susceptible
BALB/c mice with L. infantum, it was observed that the
CD4+CD25+ Treg cells rapidly expand in infected lymph
nodes and spleen cells along with an increased parasite load.
In addition to which, several characteristic Treg cell surface
markers (FoxP3, CD25, GITR, CD103) were concurrently
transcribed at 7 days after infection, underlining the
involvement of these cells during this infection. At this
specific time point, a substantial decrease in IL-4 secretion
from the CD4+CD25- effector T cell subset harvested from
the lymph nodes and splenocytes of infected mice was
observed. This suggests that Treg cells undergoing expansion
during this stage of the infection were suppressing the Th2
effector cell population. A statistically significant increase in
IL-10 production by these same CD4+CD25- T cells was also
seen at 7 days after infection which may indicate the TR1
regulatory subset contribute, in part, to the suppression of
effector T cells [16].
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B. Trypanosomiasis
Trypanosoma brucei gambiense and T. brucei rhodesiense
are flagellate parasites responsible for the African
trypanosomiasis in humans, also known as the sleeping
sickness [35]. T. brucei gambiense is frequently found in
West and Central Africa, being responsible for a chronic
form of the disease that can develop over months and years.
T. brucei rhodesiense, a less common species, is often found
in East Africa and is associated with severe acute forms of the
disease. African trypanosomiasis caused by T. b. rhodesiense
is a zoonotic disease, in which asymptomatic wild and
domestic animals act as reservoirs [36].
African trypanosomes go through several morphologically
distinct phases during their life cycle. The infection is
initiated when a haematophagous arthropod, the tsetse fly
(genus Glossina), feeds on a vertebrate host. During the
blood meal, the tsetse fly deposits metacyclic
trypomastigotes in the dermal connective tissue of the host.
The parasites rapidly reach the lymphatic and blood
circulation, replicate and develop into trypomastigotes
spreading to other locations [37]. The tsetse fly becomes
infected during feeding from an infected host. Then the
trypomastigotes replicate in the midgut and develop into
procyclic trypomastigotes. They subsequently develop into
migrating epimastigotes that attach to the salivary glands,
differentiating into metacyclic trypomastigotes to continue
the parasite life cycle in a subsequent meal [36].
African trypanosomes are very unusual amongst protozoan
parasites in that they only have parasitic extracellular stages
in the vertebrate host, persisting for extended periods of time
in the blood [37]. This characteristic makes them vulnerable
to antibody-mediated immune destruction and around 99% of
the circulating parasites are cleared from the blood by
macrophages [14, 35].
Similarly to what has been described for Leishmania
infections, some groups have shown that Treg cells are
present and might play a pivotal role controlling the outcome
of African trypanosomiasis and the persistence of the
parasite. In trypanosomiasis, the persistent infections are
accompanied by a profound immunosuppression (reviewed
by Adalid-Peralta et al. [38]).
During African trypanosomiasis, it has been reported that
the expansion of Treg cells is responsible for parasite
tolerance from the moment of establishment of infection and
continuing during chronic stage [38].
Guilliams et al. [39] showed that Treg cells influence the
outcome of the disease in trypanotolerant C57BL/6 mice.
C57BL/6 mice are considered tolerant to the disease when
infected with T. congolense, controlling the first peak of
parasitemia and developing a chronic and systemic infection.
Their results have shown an expansion of
CD4+CD25+FoxP3+ Treg cells within the CD4+ T cell
population, both in the liver and spleen of infected mice. The
expansion was verified after the first peak of parasitemia
(acute phase) and during the chronic phase. It was also
demonstrated that IL-10 produced by CD4+CD25+ Treg cells
contribute to the suppression of IFN-γ generated by CD4+
and CD8+ T effector cells, as well downregulating the
activation of macrophages. When Treg cells were depleted,
using an anti-CD25 monoclonal antibody (IL-2Rα), the
trypanotolerant C57BL/6 resistant mice decreased their
survival rate with augmented liver necrosis and consequent
loss in parasite clearance capacity [39]. These results show
that Treg cells play a fundamental role in the downregulation
of Th1 immune response during the chronic stage of
infection, preventing injury to the liver, maintaining its
parasite clearance function, and contributing to the
development of the trypanotolerant phenotype in T.
congolense-infected mice [39]. Finally, Treg cells may not
only influence the local suppressive activity and the delay of
the immune response in T. congolense infections, but also the
secretion of IL-10. In turn, it is possible that IL-10 generate a
beneficial suppressive environment for the expansion of
antigen-specific Treg cells.
More recently, the same group has shown that sustained
inflammation responsible for tissue damage and reduced
survival of T. brucei-infected C57BL/6 mice undergoing a
pathogenic infection was associated with the absence of Treg
cell expansion [40].
Nevertheless, the contribution of CD4+CD25+ Treg cells to
the survival rate and parasite persistence during
Trypanosoma spp. infections is still controversial. Studies
have shown that CD4+CD25highFoxP3+ Treg cells prevent an
early protective response in T. congolense-infected
susceptible BALB/c mice. After an optimal dose of
anti-CD25 antibody, infected mice did not develop
parasitaemia, eliminated all parasites and showed no signs of
disease [41].
American trypanosomiasis or Chagas disease is caused by
the obligate intracellular parasite Trypanosoma cruzi [36].
Insects of the family Reduviidae become infected with the
trypomastigote form when take a blood meal from an infected
mammalian host. Replicative non-infective epimastigotes
develop into trypomastigotes in the insect midgut. During the
bite, the insect normally urines and defecates leading to the
release of infective metacyclic trypomastigote forms [18].
The parasite then has access to host tissues through a
continuity lesion on the skin caused by the insect, or through
intact mucosae or conjunctivae [42]. Humans can also be
infected by the oral route with subsequent invasion of the
stomach epithelium or through the transplacental route
(reviewed by Walker et al. [18]). T. cruzi is internalized either
by nucleated host cells or phagocytized by macrophages and
dendritic cells, with further proliferation into non-flagellated
amastigotes inside cells from the skeletal muscle or
myocardium [42]. After replication, amastigote forms are
triggered to differentiate into motile flagellated
trypomastigotes [18]. The infected cells rupture releasing
new trypomastigotes into the blood and lymph, with
consequent invasion of new cells [42]. The life cycle is
complete when trypomastigotes or amastigotes, also known
to be infective, are ingested by the insect during a blood meal
and become epimastigotes again [18, 42].
The acute phase, usually not fatal, is followed by the
chronic and asymptomatic phase, during which parasite
multiplication seems to be controlled by the host immune
system [15, 43]. The parasite is not completely eliminated,
being able to persist in low numbers lifelong [15, 36, 43].
Human hosts will then serve as reservoirs [15, 43].
Replication control and persistence of the parasite during
the chronic phase is mainly due to T cell-mediated immunity
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regulating the anti-T. cruzi immune response [15, 44].
During cruzi-trypanosomiasis, Treg cells are present but
their role in the control of the immune system is still
controversial. Contrary to African trypanosomes, T. cruzi is
an obligate intracellular parasite [36]. Thus, the immune
response induced by an extracellular or by an intracellular
parasite will probably trigger different regulatory
mechanisms. Vitelli-Avelar et al. [44] were the first to
document a high frequency of CD4+CD25high Treg cells in
whole blood obtained from chronic (asymptomatic) T.
cruzi-infected human patients. Later, these results were
supported by the increased concentration of
CD4+CD25+FoxP3+ Treg cells found in chagasic patients
along with increased production of IL-10 and CTLA-4 [45,
46]. Furthermore, CD4+CD25+ Treg cell subsets expressing
characteristic Treg cell markers, such as FoxP3+, GITR and
CTLA-4 were found in the heart of T. cruzi infected mice
associated with host resistance and control of parasite
replication. When treated with anti-GITR antibody to block
the suppressor activity of Treg cells, mice suffered from
increased parasitism, myocarditis and mortality alongside
with upregulated production of TNF-α, in comparison with
controls [47]. Taken together, these results suggest that Treg
cells might play a role in the immune response against T.
cruzi infection reducing extensive effective immune
response, ultimately controlling the infection.
C. Malaria
Plasmodium spp. are parasitic protozoan responsible for
causing malaria in the tropical and sub-tropical regions
worldwide [48]. Currently, five species of the genus
Plasmodium are known to infect between 300 and 600
million humans every year, resulting in approximately 1
million deaths [49]. In developing countries such as
sub-Saharan African countries, the majority of the infections
are caused by P. falciparum responsible for cerebral malaria,
the most malignant form of the disease, which in most cases
leads to death due to severe anemia and neurological
problems [21, 48]. Malaria caused by P. vivax, known as
relapsing malaria, and P. ovale, together with P. falciparum,
are the most widespread across continents. However, after a
deep analysis Lysenko and Bejaev [50] report the presence of
P. ovale mainly in the sub-Saharan Africa and the islands of
the western pacific. Other publications also report its
presence in New Guinea and the Philippines (as reviewed by
Collins & Jeffery [51]). P. malariae and P. knowlesi have
also been associated with cases of malaria in Southeast Asia
[52]. In most cases and with the exception of a few regions,
the acute form of the non-falciparum malaria is mild and can
be controlled, persisting a chronic infection of low
parasitemia [53].
The life cycle of Plasmodium spp. parasites is complex
with different stages both in the anopheline vector and in the
human host. In general, the infection starts when a female
mosquito of the genus Anopheles feeds on a vertebrate host,
inoculating sporozoites into the host bloodstream [18].
Sporozoites, the infectious form of the parasite, rapidly reach
the liver, invade and multiply within the hepatocytes,
originating the schizonts. Schizonts rupture releasing
merozoites into the blood stream [48] that easily adhere to
and infect red blood cells (RBC). Inside RBC the parasite
expands exponentially, developing into the trophozoite stage
[38], divide asexually into mature schizonts (erythrocytic
schizogony), which in turn rupture the RBC and the
merozoite form is released into the blood stream,
consequently infecting other RBC, perpetuating the infection
[18]. Some of the merozoites forms may develop into male
and female gametocytes, the sexual erythrocytic stages.
When ingested by a female mosquito, these forms fuse in the
mosquito stomach to form motile zygotes that invade the
midgut and develop into oocysts that after rupture release
new sporozoites. The sporozoites migrate to the salivary
glands and when the anopheline female takes up a blood meal
on a vertebrate host, the parasite is transmitted continuing the
life cycle [18, 48, 54].
Pathogenesis in malaria occurs after merozoites develop in
RBC and the release of RBC cellular content activates
monocytes and macrophages [52]. Splenic and circulant
monocytes and DC activate CD4+ Th1 effector cells [55, 56],
which secrete pro-inflammatory cytokines, such as IFN-γ
[57], TNF-α, IL-1β and IL-16 [58]. As with other protozoan
parasites, host protection is rather ineffective, as Plasmodium
parasites develop evasive mechanisms to hide from the
immune system or subvert its mechanisms of action
(reviewed by Coban et al. [59]), limiting adaptive immunity
and memory acquisition. Furthermore, difficulties in
understanding the disease are also related to external and
extrinsic factors of the host itself which influence the level of
pathogenesis, such as nutritional status [60], intestinal flora
[57], age [55, 61, 62] and ethnicity.
The beginning of infection promotes the activation of the
CD4+CD25+FoxP3+ T cell subset [57, 63], inducing tolerance
and promoting homeostasis [64] through the production of
anti-inflammatory cytokines IL-10 and TGF-β. T lymphocyte
receptors (TLR) on nTreg cells might also be stimulated by
Plasmodium lipopolysacharide agonists, such as
glycosylphosphatidylinositol (GPI) or hemozoin-bound
DNA [65], and P. falciparum erythrocytic membrane protein
1 (PfEMP-1), presented by DC and macrophages [56].
Uncomplicated malaria by P. falciparum and P. vivax was
also shown to induce changes in cell number and proportions
of Treg cells and DC [66].
In human malaria, the suppression of host protection is
probably mediated by IL-10 [60]. IL-10 origin is still unclear,
but most likely secreted by different peripheral blood
mononuclear cells (PBMC), such as monocytes [49, 60],
macrophages [52], naïve and effector CD4+ T and iTreg cell
subsets [49]. Portugal et al. [67] also identified
IL-10-producing CD3+CD4+FoxP3-PBMC induced by P.
falciparum following fever in Malian children; whereas
CD4+CD25+FoxP3+ cells were only a very small contributing
fraction. Scholzen et al. [68] hypothesized that Treg cells
might be inducible by the self-regulating FoxP3-Th1
IL-10-producing cells, a mechanism also observed in L.
major-infection. TGF-β, other major suppressive cytokine is
mainly secreted by nTreg cells [69] and macrophages [70].
nTreg cells have been shown to require DC TLR-9
stimulation to be activated [71], but the role of this type of
receptors remains controversial, probably due to single
nucleotide polymorphisms (SNP) in pattern recognition
receptors (PRR) such as TLR, which result in different
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degrees of response [59]. TGF-β, IL-10 and IL-2 induce
peripheral CD4+CD25- T cells to express FoxP3 [66],
through antigen presentation by immature DCs [65, 72] and
monocytes [73]. It has been shown, however, that direct cell
contact is not always necessary for activation of FoxP3 [73],
which can gain regulatory function by stimulation from the
circulating cytokines IL-2 and IL-10. There is a puzzling
nomenclature for Treg cells in malaria, a problem which
should be addressed, as it does not facilitate elucidative
comparisons nor conclusions between studies.
As with leishmaniasis, it is the balance between effector T
cells and Treg cells that determines the severity of infection
[68, 74]. Treg cells, while preventing excess inflammation
and tissue destruction, can also inhibit the effector function of
CD4+ and CD8+ T cells, NKT and NK cells [65], resulting in
prevalence of the parasite and disease [75]. Moreover, IL-2
activated-Treg cells express high levels of B-cell lymphoma
2 (Bcl-2), which in turn prevents apoptosis. Competition for
IL-2 by Treg cells and memory T cells might be responsible
for the dimension of memory cell population, delineating the
severity of the symptoms [68]. Literature also indicates that
in malaria infection nTreg cells possibly modulate both acute
pro-inflammatory and Th1 memory responses [65].
It appears that the cause for different manifestations of
pathology is dependent on the levels of key cytokines present
at specific stages of infection [58, 66]. If Treg cells are
preferentially activated in the early stages of infection severe
malaria is more likely to occur [74]; whereas if Treg cells are
only activated in the latter stages of infection, effector
mechanisms are able to eliminate more infected RBC,
resulting in lower parasitaemias and suppressing
inflammation at later stage [60]. In the last case, severe forms
of the disease are less likely to occur.
CD4+CD25+ Treg cells have been shown to lower IFN-γ
production [76]. Depletion of CD25high cells, of which the
majority are Treg cells, protects mice from experimental
cerebral malaria, whereas depletion of FoxP3+ cells did not,
suggesting that Treg cells may suppress T cell responses of
the host [77]. It is not the depletion of Treg cells the sole
responsible for protection against cerebral malaria, probably
due to the prevalence of CD25low FoxP3+ T cells that are
retained even after treatment with anti-CD25 mAb. Cerebral
malaria is inhibited by suppression of CD4+ cells by
CD4+CD25+ Treg in mice infected with P. berghei [78].
Furthermore, they inhibit Th1 memory cells in a secondary
challenge. However, it was shown that depletion of Treg cells
resulted in increased effector T cell response against
circumsporozoite protein in the liver stage, but failed to
increase lasting memory [79]. In fact, the only individuals
who seem to develop immune memory to Plasmodium
infection are the ones living in endemic regions where they
are repeatedly bitten [67, 80].
More recently, Keswani & Bhattacharyya [81] have shown
that Th17 cells which requires both TGF-β and IL-6 to
differentiate, might play an important role in disease
progression. IL-6 together with lower levels of TGF-β
inhibits the proliferation of CD4+CD25+FoxP3+ iTreg cells,
promoting differentiation of Th17 [81, 82]. During acute
infection FoxP3+ Treg cells might be overwhelmed where
IFN-γ and IL-10 co-secreting CD4+ effector cells likely
auto-regulate themselves; however, if the parasite load is
controlled, the Bcl-2 production decreases and FoxP3+ Treg
cells suffer apoptosis [73].
D. Babesiosis
Babesiosis is an emerging zoonotic disease caused by the
intraerythrocytic protozoan from the genus Babesia [17].
This parasite has a worldwide distribution and is transmitted
by ticks. B. microti is a major cause of a malaria-like illness
in humans in several regions of North America and Europe
[83, 84]. Its life cycle occurs between the white-footed field
mouse, Peromyscus leucopus, and the deer tick Ixodes
scapularis. Humans enter the cycle when bitten by infected
ticks [85]. In Europe, B. divergens infections have been
steadily increasing since the first report in 1957 [86-88].
Among other causes, the increase of human babesiosis cases
reflects the augmented population of immunocompromised
individuals susceptible to infection, to which Babesia
infection is often lethal [89].
Babesia spp. infection starts when a tick feeds on a
vertebrate host injecting sporozoites together with saliva. The
sporozoites penetrate directly the RBC and by binary fission
develop into merozoites that, after cell lysis, are released into
the blood stream. Each merozoite is able to infect a new RBC
and their size and location vary according to the Babesia and
the host species. When a competent tick takes up a blood
meal from an infected host, ingests babesia-infected RBC
[89]. Some of these parasites will develop into gametocytes
or strahlenkorper (‘ray bodies’) and fuse in the lumen of the
digestive track originating zygotes [90]. The zygotes
penetrate the midgut cells and transform into a motile stage,
the ookinete. This stage migrates from the midgut and
invades other tissues, including the ovaries resulting in
transovarial transmission. After this point, Babesia will
develop by asexual multiplication (sporogony), differentiate
sporokinetes that invade the salivary glands, developing into
sporozoites, the infectious stage for the vertebrate host [91].
The mechanisms of immunity to Babesia parasites are
hypothesized to require both innate and adaptive immune
responses; however, the cell-mediated immune response is
considered the most important in reducing the multiplication
of Babesia within the vertebrate host and, at the same time,
probably leading to pathology [92]. To our best knowledge,
only one study suggests a possible role of the CD4+CD25+
Treg cells during Babesia infection, what contrasts with the
information available for other protozoan parasites
aforementioned. Jeong and colleagues [84] have shown that
Treg cells, in particular the CD4+CD25+FoxP3+ subset,
expand during the acute phase of disease in the spleen of B.
microti-infected mice at 7 and 11 days post-infection, in
comparison with control mice, facilitating the growth and
survival of the parasite.
In the future, it would be interesting to investigate and
clarify the role of the CD4+CD25+ Treg cells during the
infection caused by Babesia spp.
Infection by parasitic protozoan still represents major
threats to human health worldwide, and the chronic phase of
the diseases seems to be balanced in a tolerant state by Treg
ISSN 2326-3121 (Print) ISSN 2326-313X (Online)
This work has given an overview about the function of
Treg cells and highlighted the different regulatory
mechanisms by which Treg cells may influence the
homeostasis of the immune response, avoiding excessive
immunopathology during protozoan infections. Amongst all
the Treg subsets, CD4+CD25+ Treg cells are the best
characterized to date. However, there is considerable
controversy regarding the characteristics and functions of
these cells when induced by protozoan infections, and there is
no doubt that remains much to be learn for which more
research must be undertaken. In the future, more could be
gleaned from the long-term interaction between the
mechanisms of immune regulation and the parasites. Several
reports describe the involvement of CD4+CD25+ Treg cells
with the development and outcome of trypanosomiasis,
leishmaniasis, malaria and babesiosis and the persistence of
the respective parasites within the host.
With an increasing number of immunocompromised
individuals, the current insufficient medical treatments and
ineffective prophylaxis alternatives, these infections have
become of extreme importance. Great attention has also to be
given to healthy immunocompetent individuals, as these
protozoan infections are normally associated with the host’s
inability to clear chronic infection, thus acting as possible
reservoirs and contributing for the endemic populations. Any
situation that will compromise the immune system can
trigger disease reactivation and develop acute and
symptomatic stages. Therefore, there is an urgent need to
implement efficient strategies to prevent diseases caused by
protozoan parasites.
The understanding of these complex interactions would
favor the design of immunomodulator drugs or vaccines and
contribute for the development of novel of prophylactic and
therapeutic strategies.
The authors declare no competing personal or financial
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Babesiosis is an emerging, tick-transmitted, zoonotic disease caused by hematotropic parasites of the genus Babesia. Babesial parasites (and those of the closely related genus Theileria) are some of the most ubiquitous and widespread blood parasites in the world, second only to the trypanosomes, and consequently have considerable worldwide economic, medical, and veterinary impact. The parasites are intraerythrocytic and are commonly called piroplasms due to the pear-shaped forms found within infected red blood cells. The piroplasms are transmitted by ixodid ticks and are capable of infecting a wide variety of vertebrate hosts which are competent in maintaining the transmission cycle. Studies involving animal hosts other than humans have contributed significantly to our understanding of the disease process, including possible pathogenic mechanisms of the parasite and immunological responses of the host. To date, there are several species of Babesia that can infect humans, Babesia microti being the most prevalent. Infections with Babesia species generally follow regional distributions; cases in the United States are caused primarily by B. microti, whereas cases in Europe are usually caused by Babesia divergens. The spectrum of disease manifestation is broad, ranging from a silent infection to a fulminant, malaria-like disease, resulting in severe hemolysis and occasionally in death. Recent advances have resulted in the development of several diagnostic tests which have increased the level of sensitivity in detection, thereby facilitating diagnosis, expediting appropriate patient management, and resulting in a more accurate epidemiological description.
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Regulatory T cells (Treg) have been shown to restrict vaccine-induced T cell responses in different experimental models. In these studies CD4+CD25+ Treg were depleted using monoclonal antibodies against CD25, which might also interfere with CD25 on non-regulatory T cell populations and would have no effect on Foxp3+CD25- Treg. To obtain more insights in the specific function of Treg during vaccination we used mice that are transgenic for a bacterial artificial chromosome expressing a diphtheria toxin (DT) receptor-eGFP fusion protein under the control of the foxp3 gene locus (depletion of regulatory T cell mice; DEREG). As an experimental vaccine-carrier recombinant Bordetella adenylate cyclase toxoid fused with a MHC-class I-restricted epitope of the circumsporozoite protein (ACT-CSP) of Plasmodium berghei (Pb) was used. ACT-CSP was shown by us previously to introduce the CD8+ epitope of Pb-CSP into the MHC class I presentation pathway of professional antigen-presenting cells (APC). Using this system we demonstrate here that the number of CSP-specific T cells increases when Treg are depleted during prime but also during boost immunization. Importantly, despite this increase of T effector cells no difference in the number of antigen-specific memory cells was observed.
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The bovine tick Rhipicephalus microplus is responsible for severe economic losses in tropical cattle production. Bos indicus breeds are more resistant to tick infestations than are Bos taurus breeds, and the understanding of the physiological mechanisms involved in this difference is important for the development of new methods of parasite control. We evaluated differences in the transcript expression of genes related to the immune response in the peripheral blood of cattle previously characterized as resistant or susceptible to tick infestation. Crossbreed F2 Gir x Holstein animals (resistant, N = 6; susceptible, N = 6) were artificially submitted to tick infestation. Blood samples were collected at 0, 24, and 48 h after tick infestation and evaluated for transcript expression of the CD25, CXCL8, CXCL10, FoxP3, interleukin (IL)-10, and tumor necrosis factor alpha (TNFα) genes. Gene expression of CD25 (6.00, P < 0.01), IL-10 (31.62, P < 0.01), FoxP3 (35.48, P < 0.01), and CXCL10 (3.38, P < 0.05) was altered in the resistant group at 48 h compared with samples collected before infestation. In the susceptible group, CXCL8 (-2.02, P < 0.05) and CXCL10 (2.20, P < 0.05) showed altered expression 24 h after infestation. CXCL8 (-5.78, P < 0.05) also showed altered expression at 48 h after infestation when compared with samples collected before infestation. We detected a correlation between T γδ cell activity and the immunological mechanisms that result in a higher resistance to R. microplus in cattle.
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Elevated levels of regulatory T cells following Plasmodium infection are a well-reported phenomenon that can influence both protective and pathological anti-parasite responses, and might additionally impact on vaccine responses in acutely malaria infected individuals. The mechanisms underlying their induction or expansion by the parasite, however, are incompletely understood. In a previous study, Plasmodium falciparum infected red blood cells (iRBCs) were shown to induce effector-cytokine producing Foxp3int CD4+ T cells, as well as regulatory Foxp3hi CD4+ T cells in vitro. The aim of the present study was to determine the contribution of parasite components to the induction of Foxp3 expression in human CD4+ T cells. Using the surface PfEMP1-deficient parasite line 1G8, we demonstrate that induction of Foxp3hi and Foxp3int CD4+ T cells is independent of PfEMP1 expression on iRBCs. We further demonstrate that integrity of iRBCs is no requirement for the induction of Foxp3 expression. Finally, transwell experiments showed that induction of Foxp3 expression, and specifically the generation of Foxp3hi as opposed to Foxp3int CD4 T cells, can be mediated by soluble parasite components smaller than 20 nm and thus likely distinct from the malaria pigment hemozoin. These results suggest that the induction of Foxp3hi T cells by P. falciparum is largely independent of two key immune modulatory parasite components, and warrant future studies into the nature of the Foxp3hi inducing parasite components to potentially allow their exclusion from vaccine formulations.
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In malaria-naïve individuals, Plasmodium falciparum infection results in high levels of parasite-infected red blood cells (iRBCs) that trigger systemic inflammation and fever. Conversely, individuals in endemic areas who are repeatedly infected are often asymptomatic and have low levels of iRBCs, even young children. We hypothesized that febrile malaria alters the immune system such that P. falciparum re-exposure results in reduced production of pro-inflammatory cytokines/chemokines and enhanced anti-parasite effector responses compared to responses induced before malaria. To test this hypothesis we used a systems biology approach to analyze PBMCs sampled from healthy children before the six-month malaria season and the same children seven days after treatment of their first febrile malaria episode of the ensuing season. PBMCs were stimulated with iRBC in vitro and various immune parameters were measured. Before the malaria season, children's immune cells responded to iRBCs by producing pro-inflammatory mediators such as IL-1β, IL-6 and IL-8. Following malaria there was a marked shift in the response to iRBCs with the same children's immune cells producing lower levels of pro-inflammatory cytokines and higher levels of anti-inflammatory cytokines (IL-10, TGF-β). In addition, molecules involved in phagocytosis and activation of adaptive immunity were upregulated after malaria as compared to before. This shift was accompanied by an increase in P. falciparum-specific CD4+Foxp3- T cells that co-produce IL-10, IFN-γ and TNF; however, after the subsequent six-month dry season, a period of markedly reduced malaria transmission, P. falciparum-inducible IL-10 production remained partially upregulated only in children with persistent asymptomatic infections. These findings suggest that in the face of P. falciparum re-exposure, children acquire exposure-dependent P. falciparum-specific immunoregulatory responses that dampen pathogenic inflammation while enhancing anti-parasite effector mechanisms. These data provide mechanistic insight into the observation that P. falciparum-infected children in endemic areas are often afebrile and tend to control parasite replication.
Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4(+)CD25(+)) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4(+)CD25(-) T cells. Treatment with antitumor necrosis factor alpha (TNFalpha; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to "conventional" T cells. Furthermore, anti-TNFalpha treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFalpha therapy may be a further mechanism by which this disease is ameliorated.
Upon infection the host needs to mount vigorous immune response against pathogen in order to successfully control its replication. However, once the infectious agent is controlled or eliminated, host cells need to signal the immune system to slow or cease its activities. While vast knowledge has been accumulated through the years on the mechanisms involved in the initiation and effector phases of the immune responses, the pathways triggered in order to modulate or end innate and acquired immunity are becoming more evident as evidence for its relevance comes to surface. Due to its biological power, evidence has surfaced indicating that eventually pathogens may take advantage of such regulatory pathways in order to escape effector mechanisms and progress to persistence. This book will discuss several cellular pathways involved in controlling immune response in the context of infectious diseases, their biological consequences and potential "hijack" of these pathways for the benefit of pathogen leading towards pathogen persistence as opposed to clearance. © 2012 Springer Science+Business Media, LLC. All rights reserved.
Approximately 10% of peripheral CD4+ cells and less than 1% of CD8+ cells in normal unimmunized adult mice express the IL-2 receptor a-chain (CD25++) molecules. When CD4+ cell suspensions prepared from BALB/c nu/+ mice lymph nodes and spleens were depleted of CD25++ cells by specific mAb and C, and then inoculated into BALB/c athymic nude (nu/nu) mice, all recipients spontaneously developed histologically and serologically evi dent autoimmune diseases (such as thyroiditis, gastritis, insulitis, sialoadenitis, adrenalitis, oophoritis, glomerulo nephritis, and polyarthritis); some mice also developed graft-vs-host-like wasting disease. Reconstitution of CD4+ cells within a limited period after transfer of CD4+ cells prevented these autoimmune de velopments in a dose-dependent fashion, whereas the reconstitution several days later, or inoculation of an equivalent dose of CD8+ cells, was far less efficient for the prevention. When nu/nu mice were transplanted with allogeneic skins or immunized with xenogeneic proteins at the time of CD25++ cell inoculation, they showed significantly heightened immune responses to the skins or proteins, and reconstitution of CD4+ cells normalized the responses. Taken together, these results indicate that CD4+ cells contribute to maintaining self-tolerance by down-regulating immune response to self and non-self Ags in an Ag-nonspecific manner, pre sumably at the T cell activation stage; elimination/reduction of CD4+ cells relieves this general suppres sion, thereby not only enhancing immune responses to non-self Ags, but also eliciting autoimmune responses to certain self-Ags. Abnormality of this T cell-mediated mechanism of peripheral tolerance can be a possible cause of various autoimmune diseases.
The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Host immune responses in disease including malaria are finely regulated by the opposing effects of Th17 and T regulatory (Treg) cells. Here we have examined the role of Treg cells and Th17 cells during malaria infection and find that low levels of Treg cells possibly influence the outcome of infections with the lethal strain of Plasmodium berghei ANKA (PbA). In contrast, high level of Treg cells may influence the outcome of non lethal Plasmodium yoelii NXL (P. yoelii) infections. We observed decreased expressions of key regulators of Treg inductions-TGF-β, CD4IL-2 and IL-10 during PbA infection, whereas their expression remains high during P. yoelii infection. On the other hand TNF-α, IL-6, IFN-γ and IL-23 expression is high during PbA infection and lower during P. yoelii infection. Thus, results from this study suggest that the differential expression of Treg and Th17 might have a key role on host pathogenesis during malaria infection. The high level of IL-6 and low level of TGF-β may composite of the advantaged local microenvironment for the production of Th17 cells in the spleen of the PBA infected mice and vice verse during nonlethal P. yoelii.