Mechanism of T regulatory cell function

Frankel Laboratory, Center for Stem Cell Research, Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
Autoimmunity Reviews (Impact Factor: 7.93). 06/2008; 7(5):370-5. DOI: 10.1016/j.autrev.2008.03.001
Source: PubMed


Regulatory T cells (Treg) play a pivotal role in tolerance to self-antigens and tissue grafts, and suppression of autoimmune reactions. These cells modulate the intensity and quality of immune reactions through attenuation of the cytolytic activities of reactive immune cells. Treg cells operate primarily at the site of inflammation where they modulate the immune reaction through three major mechanisms: a) direct killing of cytotoxic cells through cell-to-cell contact, b) inhibition of cytokine production by cytotoxic cells, in particular interleukin-2, c) direct secretion of immunomodulatory cytokines, in particular TGF-beta and interleukin-10. In addition to differential contributions of these mechanisms under variable inflammatory conditions, mechanistic complexity and diversity evolves from the diverse tasks performed by various Treg cell subsets in different stages of the immune reaction. Here we attempt to integrate the current experimental evidence to delineate the major suppressive pathways of Treg cells.


Available from: Nadir Askenasy
This article appeared in a journal published by Elsevier. The attached
copy is furnished to the author for internal non-commercial research
and education use, including for instruction at the authors institution
and sharing with colleagues.
Other uses, including reproduction and distribution, or selling or
licensing copies, or posting to personal, institutional or third party
websites are prohibited.
In most cases authors are permitted to post their version of the
article (e.g. in Word or Tex form) to their personal website or
institutional repository. Authors requiring further information
regarding Elsevier’s archiving and manuscript policies are
encouraged to visit:
Page 1
Author's personal copy
Mechanisms of T regulatory cell function
Nadir Askenasy
, Ayelet Kaminitz
, Shai Yarkoni
Frankel Laboratory, Center for Stem Cell Research, Department of Pediatric HematologyOncology, Schneider Children's Medical Center of
Israel, Petach Tikva, 49202, Israel
Target-In Ltd, Petach Tikva, 49202, Israel
Received 19 February 2008; accepted 1 March 2008
Available online 24 March 2008
Regulatory T cells (Treg) play a pivotal role in tolerance to self-antigens and tissue grafts, and suppression of autoimmune
reactions. These cells modulate the intensity and quality of immune reactions through attenuation of the cytolytic activities of
reactive immune cells. Treg cells operate primarily at the site of inflammation where they modulate the immune reaction
through three major mechanisms: a) direct killing of cytotoxic cells through cell-to-cell contact, b) inhibition of cytokine
production by cytotoxic cells, in particular interleukin-2, c) direct secretion of immunomodulatory cytokines, in particular TGF-
β and interleukin-10. In addition to differential contributions of these mechanisms under variable inflammatory conditions,
mechanistic complexity and diversity evolves from the diverse tasks performed by various Treg cell subsets in different stages
of the immune reaction. Here we attempt to integrate the current experimental evidence to delineate the major suppressive
pathways of Treg cells.
© 2008 Elsevier B.V. All rights reserved.
Keywords: T regulatory cells; Immune homeostasis; Mechanisms of suppression; Activation induced cell death; Interleukin-2; Immunomodulatory
1. T regulatory cells ................................................... 371
2. Treg cells operate at sites of inflammation ...................................... 371
3. Mechanisms of Treg cell function .......................................... 372
4. The question of antigen specificity .......................................... 373
5. Summary ....................................................... 374
Take-home messages .................................................... 374
Acknowledgments ..................................................... 374
References ......................................................... 374
vailable online at
Autoimmunity Reviews 7 (2008) 370 375
Corresponding author. Shenkar Street 14, Petach Tikva, Israel. Tel.: +972 3 925 6760; fax: +972 3924 1346.
E-mail address: (S. Yarkoni).
1568-9972/$ - see front matter © 2008 Elsevier B.V. All rights reserved.
Page 2
Author's personal copy
1. T regulatory cells
Among numerous subsets of regulatory T (Treg) cells
involved in homeostasis of the immune system, CD4
T cells with regulatory functions have
attracted much attention in recent years. The new
information on the function of innate Treg cell subsets
led to intensive experimental work and an equal number
of reviews that synthesize the information, attempting to
design more physiological ways of immunomodulation.
The bes t-characterized naturally occurrin g murine
T cells that develop in the thymus
[1] play a pivotal role in the maintenance of immuno-
logical self-tolerance and the modulation of immune
responses [24]. In addition to the innate subsets,
adaptive Treg cells are extrathymically derived from
peripheral CD4
T cells following antigenic stimulation
[5]. The activity of all these subsets is orchestrated with
the effector T cells within an intricate network of
physiological immune homeostasis.
Phenotypic ch aracterization of the different T reg subsets
is important for isolation, character ization , ex vivo expan-
sion and in vivo tracking their activity. While it is
conceivable that T reg cells use the molecular pathways
prevalent in the immu ne system, a varie ty of molecule s
have been associated with various aspects of their sup-
pressive activities. Although most of these molecules are
not specific markers of the regulatory T cell subsets, they
are potential tar gets for in tervent ions aiming to modulate
their regulatory functions. Under physiological conditions,
the high-affinity α chain of the IL-2 receptor (CD25) is
expressedin510% and 1% of peripheral CD4
and CD8
T cells, respectively. The naturally occurring CD4
T reg subset is considered to represent a developmentally
distinct T cell lineage, which is pre-programmed to perform
suppressive tasks [6]. However , the expression of CD25 in
T reg and Teff cells is variable. Qualitatively, all T cells
upregulate significantly IL-2 receptor (IL-2R) expression
upon activation, as a central mechanism of propagation of
immune reactivity. Because the high-affinity IL-2R is a
specific and general marker of recently activated T cells, it
best dissociates stimulated cells from the inactive and
memory T cells [5]. Thus, the presence of CD25 as part of
IL-2R on the cell surface, considered as a phenotypic
marker of a subset of T reg cells, has poor specificity under
conditions of immune activation. Quantitatively, the
transient expression of CD25
upon activation of effector
T cells (Teff) is significantly lower than that observed in
innate T re g cells (CD25
) [1,6]. This marker is even less
reliable in adaptive T reg cells which downregulate CD25
expression following in vivo stimulation. T reg cells with a
phenotype endowed with potent suppressive
activity in diabetes and transplant models present extreme
cases of CD25 variability [7,8].
The high-affinity IL-2R α-subunit (CD25) is often
associated with the transcription factor X-linked forkhead /
winged helix (FoxP3) [25]. FoxP3 plays a key functional
role in the develo pment of CD4
T reg cells, as mice
with natural or induced mutations in this gene display
deregulated immunity and develop severe multiorgan
inflammatory diseases [9]. Among the many types of
regulatory cells, the Foxp3
T cells emerge as key players
in the maintenance of self-tolerance, and its expression
appears to be a more sensitive parameter that dissociates
between activated CD4
Teff cells and CD4
T reg cells. Recent studies showed that some
adaptive Treg cells lose their CD25 expression in vivo but
retain FoxP3 expression [9], suggesting that this transcrip-
tion factor is a marker with better sensitivity for T reg cell
identification. However , it is likely that CD25 and FoxP3
identify different subsets of cells, because not all CD25
cells stain positive for FoxP3, and inversely, not all FoxP3
cells are positive for CD25. Although FoxP3 is an
inductive transcription factor of CD25 expression, its up-
regulation secondary to TCR engagement in the presence
of TGF-β was not necessarily related to a suppressive
phenotype of the cells [10]. In view of the phenotypic
infidelity of T reg cells, it is questioned whether they share
common effector pathways of immune suppression [1 1].
2. Treg cells operate at sites of inflammation
Regulatory T cells operate primarily at the site of
inflammation, in close spatial proximity to and through
direct interaction with the effector cells. A requirement of
cell-to-cell contact to achieve Tre g-mediate d immunomo-
dulation was convincingly demonstrated in in vitro
experiments [12]. Direct interaction with the pathogenic
cells places the Treg cells at the sites of inflammation,
despite weaker chemotactic responses of naïve CD25
T reg cells as compared to the chemotaxis of CD2 5
pathogenic T cells [13]. This pattern of behavior was nicely
demonstrated by the inefficient penetration of Treg cells
into the pancreas of NOD.SCID mice without co-transfer
of diabetogenic T cells [8], suggesting that inflammatory
signals were required to attract the regulatory cells [14].
The need for signals of inflammation from the pancreatic
lymph nodes and islets, along with demonstration that
physical co-localization with Tef f cells is essential to
achieve a suppressive activity was established in a number
of diabetes models in vivo [14,15]. The evolving scenario
implies that T reg cells are attracted to sites of inflammation
after homing of the Te ff cells. Subsequently, the chemo-
tactic receptors of T reg cells are downregulated and
371N. Askenasy et al. / Autoimmunity Reviews 7 (2008) 370375
Page 3
Author's personal copy
adhesive interactions arrest their migration [16].Fromthe
experimental point of view this is a very important aspect,
because analysis is frequently performed on cells harvested
from the spleen or mesenteric lymph nodes that contain
large numbers of cells. However , these sites may not
adequately reflect the activity of T reg cells and may include
generalized reactive modulation of immunity secondary to
an ongoing inflammati on at a remote site.
3. Mechanisms of Treg cell function
Upon homing to the site of inflammation, Treg cells
operate in concert with Teff cells in modulation of the
immune reaction. Three distinct mechanisms appear to
mediate the suppressive effect of Treg cells on cytolytic
cells, with variable contributions under different experi-
mental conditions and inflammatory environments. All
these mechanisms require close spatial proximity between
the suppressor and suppressed cells, either in the target
tissue or the regional lymph nodes. The first mechanism
involves physical elimination of cytotoxic cells, by direct
cell-to-cell contact at the site of inflammation. For example,
T reg cells directly kill the effector cells in the regional
lymph nodes and target tissues [17,18], with prefe rential
use of perforin/granzyme by naturally occurring Treg cells
and of Fas-ligand (FasL) by adaptive Treg cells [18,19].
This mechanism may be dominant in situations where the
induction of tolerance depends on functional apoptotic
pathways. For example, induction of oral tolerance through
initiation of a subset of immunomodulatory cells depends
on functional Fas/FasL signaling [20].Inmodelsof
autoimmune diabetes, Treg cells use FasL to deplete the
Th1 effector cells in lymphoid tissues, and FasL inhibition
results in persistence of the diabetogenic cells [18].Fas-
mediated apoptosis is critical both to the induction of
tolerance via apoptosis of antigen-reactive lymphocytes,
and also to the maintenance of tolerance through polariza-
tion of the immune response towards protectiv e Th2
responses [18,21]. For example, induction of T reg cells that
keep in check new thymic emigrants with allogeneic
reactivity underscores the important role of Fas/FasL-
mediated apoptosis in the development and function of
immunoregulatory T cells and cytokines [20]. However, it
should be noted that suppressive functions of T r eg cells do
not always require physical elimination of Teff cells, as
demonstrated in other autoimmune models where Treg
cells only repressed the cytolytic functions of Teff cells
The second mechanism involves inhibition of prolif-
eration and/or cytokine production in pathogenic T cells
[22,23]. Although proliferation is a good predictive factor
of cytotoxic T cell reactivity, these functions are dif-
ferentially affected by Treg cells under various experi-
mental conditions. On the one hand, Treg cells repress the
cytolytic capacity of Teff cells after antigen-specific sen-
sitization by decreasing cytokine production, without
affecting their proliferation [7]. This regulatory mechan-
ism may involve various cytokines and chemokine recep-
tors, such as suppression of INF-γ-dependent CXCR3
expression in Teff cells, reducing their ability to home to
the pancreatic lymph nodes of diabetic mice [24].The
most important factor is inhibition of IL-2 production in
the earliest stages of Teff cell activation that results in
anergy, before and without obligatory suppression of Teff
cell expansion [6,22,23]. On the other hand, the activity of
Treg cells was associated with inhibition of Teff cell
proliferation. For example, using T cells with a rearranged
transgenic TCR it was demonstrated that (antigen-
stimulated) Treg cells block the migration, expansion
and IL-2 production of Teff cells [25]. Mitotic activity was
restored by antigen stimulation of the Teff cells, but only
partially by exogenous supplementation of IL-2, indicat-
ing that inhibited secretion of this cytokine was only
partially responsible for the mitotic block [25]. Subse-
quent studies showed that the refractory state of Teff cells
to IL-2 signaling is uncoupled from the mitotic machinery
in the presence of competent IL-2 receptor ligation [26].
These data suggest that Treg cells can differentially
suppress the cytolytic and proliferative activities of Teff
cells by inhibition of their cytokine production. Impor-
tantly, a direct inhibitory effect on Teff cells can be
induced prior to onset of cell proliferation.
In addition to the contextual association of T reg cells
with CD25 expression, IL-2 plays an important role in
suppression of the immune reaction. Regulatory T cells
attenuate IL-2 homeostasis in two ways: inhibition of IL-2
production and/or excessive IL-2 consumption. Both a re
significant mechanisms of Treg cell-mediated suppression
of CD4
and CD8
T cells upon TCR stimulation
stages of cytotoxic T cell activation induces anergy [6,22],
with [25,26] and without [7] concomitant blockade of Te ff
cell expansion in vitr o and in vivo. The sec ond pathway
involves a paracrine depletion of IL-2 that impairs the
cytolyti c activit y and expansion of reactive Teff cells [28].
Despite constitutive expression of CD25 by most Foxp3
T reg cells, naturally occurring T reg cells do not secrete IL-2
[24], while adaptive T r eg cells secrete this cytokine
[5,18]. Quantitatively, innate T reg cells depend primarily
on IL-2 secreted by reactive T cells and to a lesser extent on
IL-2 released by other cell types [29]. Thus, within the
competition for IL-2, avid consumption of Treg cells [28]
depletes the availability of this cytokine to the expanding
clones of Tef f cells. It should be noted that IL-2 induces
372 N. Askenasy et al. / Autoimmunity Reviews 7 (2008) 370375
Page 4
Author's personal copy
expression of its receptor (including the α chain) as a
positive feedback mechanism in activated T cells [30].
The third mechanism involves modulation of the
cytokine environment at the site of inflammation through
direct secretion of cytokines. CD25
T reg cells
produce immunoregulatory molecules such as TGF-β and
IL-10, which directly affect the activity of cytotoxic T cells
and antigen presenting cells (APC). TGF-β1reduces
cytokine secretion by activated CD4
Tcells[31], without
limiting their capacity to expand and without inducing their
apoptosis [32].TGF-β1 also induces IL-10 production in
Th1 cells [32], which further inhibits cytokine production
and directly attenuates Teff cell function [33].Ina
reciprocal interaction, IL-10 enhances the response of
activated T cells to TGF-β1throughregulationofTGF
receptor expression [32]. Thus, combined effects the TGF-
β and IL-10 inhibit the activity of Teff cells with minor
effect on their expansion. In addition, the local cytokine
composition indirectly affects the intensity of the immune
reaction through modulation of the behavior of APC. Both
TGF-β and IL-10 are released after phagocytosis of
apoptotic cells by dendritic cells (DC) and macroph ages
[34]. IL-10 downregulates APC production of IL-12 (an
inductive cytokine for APC) and further inhibits the
differentiation and responses of Th1-type cells [34].In
parallel, interaction of T cells with APC triggers IL-2
production in the latter, which acts to enhance reactive T
cell proliferation. Thus, IL-10 released by the T reg cells
directly downsizes the activity of APC (through IL-12),
and indirectly lowers the intensity of entire immune
reaction through inhibition of IL-2 production. As expected
from cy tokine-mediated modulation of the inflammatory
environment, the ensuing qualitative and quantitative
changes in microenvironmental cytokines composition
impose complex effects on the immune reaction. The
restrictive activities mediated by alterations in IL-2
concentrations recur to downregulate the activity of the
T reg cells, which depend on this cytokine for sustained
suppressive activity in the periphery [24].
4. The question of antigen specificity
Naturally occurring Treg cells are mitotically quiescent
under basal conditions, displaying proliferative anergy
according to the Teff vocabulary [6,27].IneffectorTcells,
proliferation is the best evidence of functional activation. In
contrast, the proliferative and suppressive functions appear
to be parameters with discrete regulation in Treg cells.
Innate T reg cells are a distinct thymic subset programmed
for immunosuppressive tasks, which require antigenic
stimulati on to initiat e proliferation in vivo [6,13], but do not
require engagement of major histocompatibility complex
(MHC) antigens to trigger their suppressive activity [35].
High CD25 expression and intermediate/low CD45RB
expression suggests that most of the (non-proliferating)
innate Treg cells are functionally primed [6,16], and do not
always depend on TCR engagement when executing their
suppressive activity [6,13]. Thus, antigen-sp ecific, TCR-
mediated sensitization is required to induce proliferation,
and to a lesser extent to activate the suppressive function of
Treg cells in vivo. Nevertheless, T reg cell expansion is an
important functional parameter, considering that the
suppressive activity of proliferating cells was 4-fold more
efficient than that of non-cycling cells, despite down-
regulation of CD25 upon in vitro stimulation [13].
The nature of TCR engagement and the requirement for
antigenic stimulation appear to be lar gely dependent on the
environment under which the T r eg cells operate. On the
one hand, activity of Treg cells at the site of inflammation
in vivo [8,15, 17], and the demonstrated need to establish
cell-to-cell contacts in vitr o [8,12] suggest an antigen-
specific mode of function of Treg cells. Indeed, antigen-
specific functions were implied by the dependence of Treg
cells on TCR engag ement to acquire full in vivo sup-
pressive activity in the transplant and autoimmune settings
[36,37]. Furthermore, Treg activation by APC elicits a
reaction 10-fold more potent against the presented antigens
than against third party antigens [38]. On the other hand,
under various experimental conditions antigen specificity
is less accentuated, as professional Treg subsets do not
always require further stimulation under selected condi-
tions [38]. Antigen specific activity of T reg cells is disputed
in some transplant models and in immune colitis [22].
Likewise, polyclonal T reg cells effectively block auto-
immunity [22], allograft rejection and graft versus host
(GVH) reactions [39]. Efficient prevention of GVH by
T reg stimulated against third party antigens [40] and the
lack of functional specificity in autoimmune disorders
[6,22] suggest that immune regulation can be achieved in
an antigen-in dependent manner.
Taken together , these findings suggest that antigenic
stimulation is required for initiation of T reg cell pro-
liferation, whereas functional activation (suppressive
function) does not necessarily require TCR engagement.
This has significant implications that may explain the
relative insensitivit y of Tr eg cells to activation induced cell
death (AICD) following stimulation without TCR engage-
ment [26,27,37, 39]. According to this scenario, it remains
to be explained how T reg act differentially in abrogation of
GVH reactions, without losing the graft versus tumor
(GVT) activity [39]. There are two possible explanations.
First, the observation that CD4
T reg cell activation
does not require engagement of MHC class II antigens [35],
suggests that sensitization to minor antigens is in part
373N. Askenasy et al. / Autoimmunity Reviews 7 (2008) 370375
Page 5
Author's personal copy
responsible for the efficient anti-GVH activity. Minor
antigens are often the primary and most important stimuli
in the GVH disease, and may serve as a potent stimuli for
T reg cells. Second, adaptive Treg cells recruit additional
innate Treg may cells to the site of inflammation. Thus, the
numeric advantage of the latter may underlie the claim that
the suppressive function of Treg cells is antigen non-
specific . These fun ctions remain to be better defined, as
often in vitro assays fail to accurately simulate the
physiological conditions. For example, one possible bias
is the observation that TCR engagement is not a ubiquitous
activator of Treg cell proliferation in vitro [22,27],whereas
cycling is induced in vivo [6,13].
5. Summary
Among numerous interactions between cytotoxic and
T reg cells described in both in vitro and in vivo experi-
mental settings, three major mechanisms evolve as primary
mediators of suppression. First, Treg cells physically elimi-
nate cytotoxic T cells within andinproximity(regional
lymph nodes) to the site of inflammation. The use of
molecular mechanisms such as Fas-ligand and perforin/
granzyme suggest that this process is part of the negative
control of clonal expansion of cytotoxic cells through acti-
vation induced cell death. Second, Treg cells inhibit the
secretion of cytokines involved in perpetuation of the im-
mune reaction, in particular IL-2. Third, T reg cells secrete
immunomodulatory cytokines that alter the composition of
the inflammatory environment. Both latter mechanisms
directly affect the reactive capacity of Teff cells, and operate
indirectly through antigen presenting cells. It is physiolo-
gically significant that Treg cells exert complex and diverse
suppressive activities that are disease specific and change
continuously along the development and termination of
immune reactions.
Take-home messages
Phenotypic characteriza tion of Treg cells involved in
immune homeostasis is unreliable and changes under
stimulatory conditions
Treg cells operate at the site of inflammation
Treg cells physically eliminate cytotoxic T cells
Treg cells inhibit cytokine production and induce
anergy in cytotoxic T cell s
Treg cells attenuate the cytokine composition of the
inflammatory environment
Treg cells operate in antigen-specific and nonspecific
modes under variable conditions.
Antigenic stimulation affects differentially the sup-
pressive function and proliferation of Treg cells.
This study was supported by grants from the Leah and
Edward M. Frankel Trust for Experimental Bone Marrow
Transplantation. We apologize for a significant number of
relevant references to excellent work that were excluded
due to space limitations.
[1] Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Im-
munologic self-tolerance maintained by activated Tcells expressing
IL-2 receptor a-chains (CD25). Breakdown of a single mechanism
of self-tolerance causes various autoimmune diseases. J Immunol
[2] Malek TR, Bayer AL. Tolerance, not immunity, crucially de-
pends on IL-2. Nat Rev Immunol 2004;4:66574.
[3] Nelson BH. IL-2, regulatory T cells, and tolerance. J Immunol
[4] Fehervari Z, Yamaguchi T, Sakaguchi S. The dichotomous role of
IL-2: tolerance versus immunity . T rends Immunol 2006;27:10911.
[5] Bluestone JA, Abbas AK. Natural versus adaptive regulatory T
cells. Nat Rev, Immunol 2003;3:2537.
[6] Kuniyasu Y, Takahashi T, Itoh M, Shimizu J, Toda G, Sakaguchi
S. Naturally anergic and suppressive CD25
T cells as a
functionally and phenotypically distinct immunoregulatory T cell
subpopulation. Int Immunol 2000;12:114555.
[7] Wood KJ, Sakaguchi S. Regulatory T cells in transplantation
tolerance. Nat Rev, Immunol 2003;3:199210.
[8] Chen Z, Herman AE, Matos M, Mathis D, Benoist C. Where
CD4 + CD25 + T reg cells impinge on autoimmune diabetes.
J Exp Med 2005;202:138797.
[9] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the
development and function of CD4 + CD25 + regulatory T cells.
Nat Immunol 2003;4:3306.
[10] Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3
expression in naive human CD4 + FOXP3- T cells by T cell
receptor stimulation is TGF{beta}-dependent but does not confer
a regulatory phenotype. Blood 2007;110:298390.
[11] Miyara M, Sakaguchi S. Natural regulatory T cells: mechanisms
of suppression. Trends Mol Med 2007;13:10816.
[12] Piccirillo CA, Letterio JJ, Thornton AM, et al. CD4 + CD25 +
regulatory T cells can mediate suppressor function in the absence
of transforming growth factor ß1 production and responsiveness.
J Exp Med 2002;196:23746.
[13] Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A.
Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells
in vivo. Nat Immunol 2002;3:3341.
[14] Siegmund K, Feuerer M, Siewert C, et al. Migration matters:
regulatory T-cell compartmentalization determines suppressive
activity in vivo. Blood 2005;106:3097104.
[15] Green EA, Choi Y, Flavell RA. Pancreatic lymph node-derived
CD4 (+) CD25 (+) Treg cells: highly potent regulators of diabetes
that require TRANCE-RANK signals. Immunity 2002;16:18391.
[16] Lim HW, Broxmeyer HE, Kim CH. Regulation of trafficking
receptor expression in human forkhead box P3
regulatory T
cells. J Immunol 2006;177:84051.
[17] Banz A, Pontoux C, Papiernik M. Modulation of Fas-dependent
apoptosis: a dynamic process controlling both the persistence and
death of CD4 regulatory T cells and effector T cells. J Immunol
374 N. Askenasy et al. / Autoimmunity Reviews 7 (2008) 370375
Page 6
Author's personal copy
[18] Weber SE, Harbertson J, Godebu E, et al. Adaptive islet-specific
regulatory CD4 T cells control autoimmune diabetes and mediate
the disappearance of pathogenic Th1 cells in vivo. J Immunol
[19] Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ. Cutting
edge: contact-mediated suppression by CD4+CD25+ regulatory
cells involves a granzyme B-dependent, perforin-independent me-
chanism. J Immunol 2005;174:17836.
[20] Watanabe T, Yoshida M, Shirai Y, et al. Administration of an antigen
at a high dose generates regulatory CD4+ T cells expressing CD95
ligand and secreting IL-4 in the liver. J Immunol 2002;168:2188 99.
[21] Askenasy N, Yolcu ES, Yaniv I, Shirwan H. Induction of
tolerance using Fas ligand: a double-edged immunomodulator.
Blood 2005;105:1396404.
[22] Thornton AM, Shevach EM. Suppressor effector function of
CD4 +CD25+ immunoregulatory T ce lls is antigen nonspecific.
J Immunol 2000;164:18390.
[23] Piccirillo CA, Shevach EM. Cutting edge: control of CD8+ T cell
activation by CD4+CD25+ immunoregulatory cells. J Immunol
[24] Sarween N, Chodos A, Raykundalia C, Khan M, Abbas AK,
Walker LS. CD4+CD25+ cells controlling a pathogenic CD4
response inhibit cytokine differentiation, CXCR-3 expression,
and tissue invasion. J Immunol 2004;173:294251.
[25] Duthoit CT, Mekala DJ, Alli RS, Geiger TL. Uncoupling of IL-2
signaling from cell cycle progression in naive CD4+ T cells by
regulatory CD4+CD25+ T lymphocytes. J Immunol
[26] Inaba H, Geiger TL. Defective cell cycle induction by IL-2 in
naive T-cells antigen stimulated in the presence of refractory T-
lymphocytes. Int Immunol 2006;18:104354.
[27] Takahashi T, Kuniyasu Y, Toda M, et al. Immunologic self-tolerance
maintained by CD25
naturally anergic and suppressive T
cells. Int Immunol 1998;10:196980.
[28] Scheffold A, Huhn J, Hofer T. Regulation of CD4+CD25+
regulatory T cell activity: it takes (IL-)two to tango. Eur J Immunol
[29] de la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is
essential for CD4
regulatory T cell function. Eur
J Immunol 2004;34:24808.
[30] Kim HP, Kelly J, Leonard WJ. The basis for IL-2-induced IL-2
receptor alpha chain gene regulation: importance of two widely
separated IL-2 response elements. Immunity 2001;15:15972.
[31] Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. Natural
and induced CD4
cells educate CD4
cells to
develop suppressive activity: the role of IL-2, TGF-b, and IL-10.
J Immunol 2004;172:521321.
[32] Cottrez F, Groux H. Regulation of TGF-beta response during T cell
activation is modulated by IL-10. J Immunol 2001;167:7738.
[33] Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa
TC, Cumano A, Bandeira A. CD25+ CD4+ T cells regulate the
expansion of peripheral CD4 T cells through the production of
IL-10. J Immunol 2001;166:300818.
[34] Moore KW, de Waal-Malefyt R, Coffman RL, O'Garra A.
Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol
[35] Bienvenu B, Martin B, Auffray C, Cordier C, Becourt C, Lucas B.
Peripheral CD8+CD25+ T lymphocytes from MHC class II-deficient
mice exhibit regulatory activity. J Immunol 2005;175:24653.
[36] Kingsley CI, Karim M, Bushell AR, Wood KJ . CD25+CD4+
regulatory T cells prevent graft rejection: CTLA-4- and IL-10-
dependent im munoregu lation of allo respon ses. J Immunol
2002;168:1 0806.
[37] Tang Q, Henriksen KJ, Bi M, et al. In vitro-expanded antigen-
specific regulatory T cells suppress autoimmune diabetes. J Exp
Med 2004;199:145565.
[38] Yamazaki S, Inaba K, Tarbell KV, Steinman RM. Dendritic
cells expand an tigen- specifi c Foxp3+ CD25 + CD4+ regula-
tory T cells including suppressors of allo reacti vity. Immun ol
Rev 2006;212:31429.
[39] Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S.
Donor-type CD4+ CD25+ regulatory T cells suppress lethal acute
graft-versus-host disease after allogeneic bone marrow trans-
plantation. J Exp Med 2002;196:38999.
[40] Steiner D, Brunicki N, Blazar BR, Bachar-Lustig E, Reisner Y.
Tolerance induction by third-party off-the-shelf CD4+CD25+
Treg cells. Exp Hematol 2006;34:6671.
Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secret ed by interleukin
27-stimulated T cells
Excessive inflammation occurs during infection and autoimmunity in mice lacking the alpha-subunit of the
interleukin 27 (IL-27) receptor. The molecular mechanisms underlying this increased inflammation are
incompletely understood. Here, Fitzgerald DC. et al. (Nat Immunol 2007; 8: 1372-9) report that IL-27
upregulated IL-10 in effector T cells that produced interferon-gamma and expressed the transcription factor T-bet
but did not express the transcription factor Foxp3. These IFN-gamma+T-bet+Foxp3- cells resembled effector T
cells that have been identified as the main source of host-protective IL-10 during inflammation. IL-27-induced
production of IL-10 was associated with less secretion of IL-17, and exogenous IL-27 reduced the severity of
adoptively transferred experimental autoimmune encephalomyelitis by a mechanism dependent on IL-10. This data
shows that IL-27-induced production of IL-10 by effector T cells contributes to the immunomodulatory function of
375N. Askenasy et al. / Autoimmunity Reviews 7 (2008) 370375
Page 7
  • Source
    • "Regulatory T-cells constitutively express high levels of TNFR2 [86] and the expression of TNFR2 defines a unique subtype of Tregs with highly potent suppressive activity [51]. Further studies demonstrated that activation of TNFR2 results in the generation and expansion of a subpopulation of protective regulatory T-cells that may suppress autoimmunity [84,85]. Whereas TNFR2 seems not to be necessary to maintain Treg activity, recent results suggest that TNFR2 mediates the activation of Tregs [50] and plays a functional role in their expansion [52] and stabilization [53]. "
    [Show abstract] [Hide abstract] ABSTRACT: Deregulation of the tumor necrosis factor (TNF) plays an important role in the initiation and perpetuation of chronic inflammation and has been implicated in the development of various autoimmune diseases. Accordingly, TNF-inhibitors are successfully used for the treatment of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, total inhibition of TNF can cause severe side effects such as an increased risk of inflammation and reactivation of tuberculosis. This is likely due to the different actions of the two TNF receptors. Whereas TNFR1 predominantly promotes inflammatory signaling pathways, TNFR2 mediates immune modulatory functions and promotes tissue homeostasis and regeneration. Therefore, the specific blockage of TNFR1 signaling, either by direct inhibition with TNFR1-selective antagonists or by targeting soluble TNF, which predominantly activates TNFR1, may prevent the detrimental effects associated with total TNF-inhibitors and constitute a next-generation approach to interfere with TNF.
    Full-text · Article · Mar 2015
  • Source
    • "In this sense, the functions of IL-12 also includes stimulation of specific cytotoxicity of T cells by supporting T helper cells (CD4 + ) differentiation as well as by inducing IFNg and IL-2 production by these cells (Trinchieri, 2003). Furthermore, the significant decrease of cells expressing CD25, defined as a receptor for IL-2 mainly expressed on activated conventional T cells (Askenasy et al., 2008), might be indicative of low levels of this cytokine which is involved in growth and proliferation of T cells (Malek, 2002). Therefore, the depletion of these T cell subsets together with the absence of these cytokines which play a crucial role in the regulation of cell-mediated antiviral immunity by promoting the proliferation and survival of effector T cells, suggested that both BTV-1 and BTV-8 might attempt to constrain or modulate the innate immune response as well as cell mediated immunity in host sheep at initial stage of the infection in order to favoring viral replication and spreading, thereby impairing host's capability against primary infections with BTV. "
    [Show abstract] [Hide abstract] ABSTRACT: Protective immunity in sheep with bluetongue virus (BTV) infection as well as the role of BTV-induced cytokines during immune response remains unclear. Understanding the basis immunological mechanisms in sheep experimentally infected with serotypes 1 and 8 (BTV-1 and -8) was the aim of this study. A time-course study was carried out in order to evaluate cell-mediated immune response and serum concentrations of cytokines (IL-1β, TNFα, IL-12, IFNγ, IL-4 and IL-10) with inflammatory and immunological functions. Depletion of T cell subsets (mainly CD4(+), γδ and CD25(+)) together with the absence of cytokines (IFNγ and IL-12) involved in the regulation of cell-mediated antiviral immunity at the first stage of the disease suggested that both BTV-1 and BTV-8 might impair host's capability against primary infections which would favor viral replication and spreading. However, cellular immune response and cytokines elicited an immune response in sheep that efficiently reduced viremia in the final stage of the experiment. Recovery of T cell subsets (CD4(+) and CD25(+)) together with a significant increase of CD8(+) T lymphocytes in both infected groups were observed in parallel with the decrease of viremia. Additionally, the recovery of CD4(+) T lymphocytes together with the significant increase of IL-4 serum levels at the final stage of the experiment might contribute to humoral immune response activation and neutralizing antibodies production against BTV previously described in the course of this experiment. These results suggested that both cellular and humoral immune response may contribute to protective immunity against BTV-1 and BTV-8 in sheep. The possible role played by IL-10 and CD25(+) cells in controlling inflammatory and immune response in the final stage of the experiment has also been suggested. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Feb 2015 · Veterinary Microbiology
  • Source
    • "According to our hypothesis, NHL pathogenesis starts with Th2 pathway activation. We know that the increased secretion of IL-10 by Th2 cells can promote the development of T-reg cells from T helper cells, and newly developed T-reg cells begin to secrete their own IL-10 and inhibit both Th1 and Th2 functions [3,6]. As mentioned above, IL-10 is a strong inhibitor cytokine. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: Increased risk for non-Hodgkin lymphoma (NHL) is associated with infections and environmental agents. We hypothesized that these factors chronically trigger the T helper-2 (Th2) pathway and result in lymphoma. We investigated the role of the Th2 pathway by exploring the relationships between components of the Th2 pathway, interleukin (IL)-10, IL-4, immunoglobulin E (IgE), and eosinophils, and prognostic markers of NHL. Materials and Methods: Thirty-one NHL patients and 27 healthy controls were enrolled. IL-10, IL-4, IgE, and eosinophils were measured. IL-4 and IL-10 were analyzed with the enzyme amplified sensitivity immunoassay method. Results: High IL-10 levels were correlated with several poor prognostic features, short early survival, and lymphopenia. There was a positive correlation between albumin and IL-4 levels and a negative correlation between IL-10 and albumin. There was no relationship related with eosinophils and IgE. We found remnant increased IL-4, which could be a clue for the triggering of the Th2 pathway in the background. Conclusion: There is a need for differently designed studies to detect the place of the Th2 pathway in NHL.
    Full-text · Article · Dec 2014 · Turkish Journal of Haematology
Show more