Cite this article: Simon AK, Hollander GA,
McMichael A. 2015 Evolution of the immune
system in humans from infancy to old age.
Proc. R. Soc. B 282: 20143085.
Received: 20 January 2015
Accepted: 1 May 2015
health and disease and epidemiology,
adaptive immunity, innate immunity,
Author for correspondence:
One contribution to the special feature
‘Evolution and genetics in medicine’ Guest
edited by Roy Anderson and Brian Spratt.
Invited to commemorate 350 years
of scientific publishing at the Royal
Evolution of the immune system in
humans from infancy to old age
A. Katharina Simon1, Georg A. Hollander2and Andrew McMichael3
Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, and
Department of Paediatrics,
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
Nuffield Department of Medicine Research Building, University of Oxford, Old Road Campus, Oxford OX3 7FZ, UK
This article reviews the development of the immune response through neo-
natal, infant and adult life, including pregnancy, ending with the decline in
old age. A picture emerges of a child born with an immature, innate and adap-
tive immune system, which matures and acquires memory as he or she grows.
It then goes into decline inold age. These changes are considered alongside the
risks of different types of infection, autoimmune disease and malignancy.
And one man in his time plays many parts,
His acts being seven ages.
More than 1600 genes are involved in innate and adaptive immune responses .
These genes are of great importance for sustaining life in a hostile environment. Yet
the immune system is relatively immature at birth and has to evolve during a life of
exposure to multiple foreign challenges through childhood, viayoung and mature
adulthood (including pregnancy), to the decline of old age (figure 1).
2. Ontogeny of the immune system in early life
At first the infant,
Mewling and puking in the nurse’s arms.
In utero, the fetal environment demands that the immune system remains tolerant
to maternal alloantigens. After birth, the sudden enormous exposure to environ-
mental antigens, many of them derived from intestinal commensal bacteria, calls
for a rapid change to make distinct immune responses appropriate for early life.
(a) The innate immune system
The innate immune system provides an early first line of defence against invading
pathogens. The cells involved are neutrophils, monocytes, macrophages and den-
dritic cells, which all interact with the adaptive immune system. These cells
develop and mature during fetal life, but at different times, and the function of
all components of innate immunity is weak in newborns compared with later life.
Mature neutrophils are present at the end of the first trimester and steeply
increase in number, stimulated by granulocyte-colony-stimulating factor, shortly
before birth. Their number then returns to a stable level within days, but they
show weak bactericidal functions, poor responses to inflammatory stimuli,
reducedadhesion to endothelial cells anddiminished chemotaxis . These deficits
are more striking in preterm infants, which also have lower serum IgG and comp-
lement. Consequently, the newborn, and especially premature infants, have
impaired neutrophil functions , putting the child at risk of bacterial infections.
In preterm and newborn infants, classical monocytes and macrophages are
also immature. They have reduced TLR4 expression  with impaired innate
&2015 The Authors Published by the Royal Society under the terms of the Creative Commons Attribution
License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original
author and source are credited.
signalling pathways [6– 8], resulting in diminished cytokine
responses compared with adults. Consequently, there is poor
tissue repair, impaired phagocytosis of potential pathogens
and poor secretion of bioactive molecules. However, while
there is a reduced frequency of pulmonary macrophages in pre-
mature and term infants, adult levels of these cells are reached
within days after birth .
Compared with blood from children or adults, cord blood
contains fewer myeloid-type dendritic cells (mDC). They
express lower cell surface levels of HLA class II, CD80 and
CD86 than adult mDC . They secrete low concentrations
of IL-12p70 in response to activating innate stimuli . Thus
priming of Th1 and CD8 T-cell responses is diminished com-
pared with adults, correlating with an increased susceptibility
to infections caused by viruses, Mycobacterium tuberculosis and
Salmonella spp.In contrast, newborn mDC stimulated via
TLR4 secrete adult-like concentrations of pro-inflammatory
cytokines  that promote Th17 immune responses.
Plasmacytoid dendritic cells (pDC) release high concen-
trations of type I interferon (IFN) in response to TLR7 and
TLR9 stimulation in adults. However, newborn pDC are severely
limited in secreting interferon a/bupon exposure to different
viruses, despite expressing levels of TLR7 and TLR9 that are
similar to adults . Consequently, innate immune responses
to viruses such as respiratory syncytial virus, herpes simplex
virus and cytomegalovirus are poor compared with later in life.
Natural killer (NK) cells in adults restrain viral replication
and dissemination before adaptive immunity is established
. They are regulated by inhibitory receptors that recognize
HLA-A, B, C and E, and therefore contribute to self-tolerance.
In early gestation, NK cells are hypo-responsive to target cells
lacking major histocompatibility complex (MHC) class I mol-
ecules (such as trophoblast ) and are highly susceptible
to immune suppression by transforming growth factor-b
(TGF-b). NK cytolytic function increases during gestation but is
still only half of adult level at birth. Neonatal NK cells are less
responsive to activation by IL-2 and IL-15, and produce limited
IFN-gconcentrations. However, the cells’ threshold for activation
is lower, which provides some anti-viral protection .
The three independent pathways that activate the comp-
lement system are critical to host defence and inflammation.
Complement components facilitate opsonization, are chemo-
attractants for innate cells, mediate cell lysis and influence anti-
body production. Newborn serum concentrations of almost all
circulating components are 10–80% lower than in adults ,
with diminished biological activity. Complement levels
increase after birth,with some serum factors reaching adult con-
centration within a month (e.g. Factor B), but others evolve
more slowly . Because infants have low immunoglobulin
concentrations, complement effector functions depend on the
alternative and lectin-binding activation pathways, triggered
by polysaccharides and endotoxins.
110 20 30 40 50 60 70 80 90
110 20 30 40 50 60 70 80 90
deaths per 1000 persons
strength of the response
B and innate
Figure 1. (a) The seven ages of woman. (b) Schematic graph of excess deaths from seasonal or pandemic influenza over the lifetime of an individual represented as
number of deaths per 1000 persons (adapted from ). Note that while pregnancy increases the risk of severe influenza, in severe pandemics such as 1918/1919
there were also excess deaths in previously healthy young adults who were not pregnant. (c) Schematic graph of the different arms of the immune response to
influenza over the lifetime of an individual.
rspb.royalsocietypublishing.org Proc. R. Soc. B 282: 20143085
Overall, the innate immune system is muted at birth, a
price probably paid by the fetus not only to tolerate non-
shared maternal antigens but also to ignore the considerable
amount of stress and remodelling that takes place during
development. This makes the newborn, and particularly
the premature baby, relatively susceptible to bacterial and
(b) The adaptive immune system
T cells develop in the thymus, which is largest at birth and
during the first years of life. Mature single CD4
positive T cells are first detected in the thymus at week 15
and abundant in the periphery well before birth [17,18]. How-
ever, neonatal T cells differ significantly from adult cells,
reflecting the fetal life, where exposure to foreign antigens is lar-
gely restricted to non-inherited maternal alloantigens. The
function of early-life T cells is different from adult T cells.
For example, though fetal naive CD4
T cells respond
strongly to alloantigens, they tend to develop towards Foxp3
regulatory T cells (T
) through the influence of
TGF-b, and thus actively promote self-tolerance. Peri-
represent around 3% of total CD4
T cells at birth
 and these cells persist for an extended period of time ,
giving the early-life immune response an anti-inflammatory
Foreign antigen activation of late fetal or neonatal T cells
results in a response skewed towards Th2 immunity ,
which is reinforced by neonatal dendritic cells and epigenetic
features [24,25]. Very early-life adaptive T-cell immunity is thus
characterized by tolerogeneic reactivity, reduced allo-antigen
recognition and poor responses to foreign antigens.
In the newborn, in addition to conventional T cells that
recognize peptide antigens in the context of classical MHC
molecules, there are populations of gd T-cell receptor (TCR)-
positive and innate-like ab TCR-positive T cells. These include
functionally competent iNKT cells that rapidly produce IFN,
mucosal-associated invariant T (MAIT) cells  and the
newly described interleukin-8 (CXCL8)-secreting naive T cells
that bridge innate and adaptive immunity . MAIT cells
develop in the thymus, but their maturation can take place in
fetal mucosal tissues before microbial colonization. The
CXCL8-producing T cells produce important effector functions
in human newborns as they have the potential to activate
antimicrobial neutrophils and gd T cells. They appear to be par-
ticularly active at the mucosal barriers of premature and term
infants, though their frequency decreases with age. In contrast
to adult blood, wherethe repertoire ofgd TCR is restricted, neo-
natal blood gd T cells display a variety of receptor chain
combinations that change with gestation . gd T cells can pro-
duce significant amounts of IFN-g, after brief polyclonal
stimulation, compensating for the immaturity of the more
classical Th1-type T-cell response to neonatal infections [28,29].
Two types of B cell arise via distinct developmental
pathways . B1 cells spontaneously secrete low-affinity
IgM with a limited range of antigen specificities (includ-
ing common bacterial polysaccharides), have fewer somatic
mutations and serve as a first line of defence . B1 cells secrete
IL-10 and TGF-b, and thus promote a Th2 response. At birth, B1
cells comprise 40% of peripheralblood B cells and this frequency
remains high for a few months . Conventional B cells (desig-
nated B2 cells) originate from a multi-linage CD34
lymphoid progenitor and generate a broad repertoire of
immunoglobulin specificities due to their expression of terminal
deoxynucleotidyl transferase, which enhances diversity in
V-D-J immunoglobulin gene segment joining. B cells are
typically present in secondary lymphoid organs and in the
bone marrow, where they contribute to the humoral response
of the adaptive immune system.
Most antibody responses, including those to bacterial pro-
teins, bacterial polysaccharides and to polysaccharide– protein
conjugate vaccines, are dependent on T-cell help. They rely
on interactions between the TCR and the engagement of co-
receptors including CD28 and CD40 ligand on Th2 or follicular
T helper cells with their corresponding binding partners
HLA-peptide, CD80/86 and CD40 on antigen-specific B cells.
However, neonatal B cells express low levels of these co-
receptors, limiting their capacity to respond . Furthermore,
low levels of the receptor for complement C3d fragment (CD21)
impede responses to polysaccharide– complement complexes
. Together, these features contribute to blunted humoral
immune responses with incomplete immunoglobulin class
switching , although memory B cells are generated .
B cells from neonates and infants aged less than 2 months
show decreased somatic hypermutation compared with
adults, limiting affinity maturation of antibodies . Finally,
there is a failure of early-life bone marrow stromal cells to sup-
port long-term plasmablast survival and differentiation to
plasma cells, so that any IgG antibodies elicited rapidly decline
after immunization, unlike in older children and adults .
Hence, the efficiency of the adaptive immune system to respond
to T-cell-dependent antigens early is markedly impaired in neo-
nates compared with older children and adults. This
physiological behaviour is particularly relevant to vaccination
programmes. Together with the impaired innate immunity,
the weak Th1 and antibody responses amply explain why neo-
natal mortality can be high under conditions of increased
3. From childhood to adulthood
Then, the whining schoolboy with his satchel
And shining morning face, creeping like snail
Unwillingly to school.
The young human child, even as the innate and adaptive
immune systems start to mature, is at risk from many patho-
genic viruses, bacteria, fungi and parasites. Nevertheless, he
or she has a good chance of survival in developed countries.
Before there was good nutrition, hygiene and comprehensive
vaccination, there was a high mortality in infants and young
children. In 1900, the UK infant mortality rate was 140 per
1000, falling to 7 per 1000 by 2000 . This reduction in mor-
tality was proportionally greater in infants and children
compared with other age groups . Better prevention and
control of infections accounts for most of this fall. However, in
many countries, infant mortality rates remain above 50 per
1000, giving some indication of the evolutionary pressure that
must have selected a working protective immune system. Fur-
thermore, such pressure has selected the extreme genetic
polymorphism in the MHC, which through peptide presen-
tation to T cells and NK cells is a key regulator of almost all
The immune system gradually matures during infancy.
Critical early protection against many infectious diseases
rspb.royalsocietypublishing.org Proc. R. Soc. B 282: 20143085
previously experienced by the mother is given by the passive IgG
antibody transferred from the mother transplacentally and in
milk. Once that fades away, young children become more vulner-
able to infections, though by then better armed with the maturing
innate and adaptive immune systems. The risks are now much
reduced by vaccinations, which stimulate protective immune
responses in the maturing immune system. Nevertheless, chil-
dren may still acquire viral, bacterial and parasitic infections
that have to be fought off and controlled by immune responses.
Besides promoting recovery, such antigen stimulation results in
immunological memory [41,42]. Thus, over time, protection pro-
vided by the immune response increases, and young adults
suffer fewer infections. This accumulation of immunological
memory is an evolving feature of the adaptive immune response.
The memory persists into old age  but then may fade.
Besides frank infections and vaccinations, the newborn is
exposed to other antigens. He or she comes from a relatively
sterile environment in utero and is then rapidly exposed to
multiple microbes . The first major exposure to bacteria
is during passage through the birth canal, and then as soon
as he/she makes oral, skin and respiratory contact with the
exterior. From then on, exposure to microorganisms is con-
tinuous. Many of the bacteria that colonize the gut and
other mucosal sites are essential for healthy life, including
digestion of food and acquisition of vital nutrients. They
also impact on the development of the immune system .
Approximately 20% of all lymphocytes reside in the
gut , exposed to many possible foreign immunogens.
Gut immune cells monitor the boundary with a potentially
dangerous source of infections. Gut bacteria influence the
development of Th17 cells , T
cells  and memory
T cells [48–50]. At birth, nearly all T cells carry the CD45RA
glycoprotein, typical of naive T cells, which have never
encountered foreign antigen. There are also relatively abun-
within the CD45RA negative CD4 T cells. During
cell numbers decline, and memory Th1,
Th17 and Th2 cells gradually increase to equal the number of
naive T cells . Although some of these memory T cells
could have been stimulated by infections with specific patho-
gens and by vaccinations, many may be primed by the
microbiome, not only in the gut but also in the respiratory
tract and skin. These primed memory T cells may respond to
subsequent infections through cross-reactions [48,52,53]. For
example, adults who have never been exposed to HIV-1 have
memory T cells in their repertoire that react with HIV peptides
presented at the cell surface by HLA proteins; these T cells are
likely to be reawakened should HIV infection occur [48,50],
similarly to other microbes . The cross-reactivity arises
from the discrete short (8 –15 amino acids) peptides (epitopes)
which fit into peptide-binding grooves on the HLA class I or
II molecules at the cell surface and are then recognized by T
cells. Within the microbiome sequences, there are numerous
perfect and near-perfect matches to known virus peptide
epitopes, such as those from HIV-1 [48,50]. These could easily
be responsible for generating the memory T cells specific for
pathogen epitopes the person has never encountered.
Segmented filamentous bacteria in the gut are necessary
for the development of Th17 cells  and Clostridium spp.
induce colonic T
cells [54,55]. Germ-free mice have
immunological defects, including fewer Peyers patches, smal-
ler lymphoid follicles and abnormal germinal centres in the
small intestine lymphoid tissue . This immuno-deficiency
can be corrected in a few days by adding a single mouse with
normal gut flora to a cage of germ-free animals [56,57]. Thus
animal data support the notion that the microbiome shapes
the development of both memory T and B cells.
Similar events occur for B cells. The carbohydrate antigens
of the ABO blood groups cross-react with gut bacterialantigens
and stimulate IgM antibody responses. Antibodies to the gp41
protein of HIV-1 may be derived from B cells whose antibody
receptors cross-react with a protein in Escherichia coli .
As the child grows, the immune repertoire is also shaped by
intercurrent infections and vaccinations . Pathogenic infec-
tions can be documented by symptomatic illnesses suffered
by the child or adult, but for many viruses, such as influenza,
infection may be subclinical, but still sufficient to stimulate or
boost immune responses . Generally, the protection offered
by the immuneresponse, both by antibodies and T cells, is very
potent. Most childhood infections happen only once and then
protection is lifelong.
The maintenance of long-term B-cell memory is remark-
able given that IgG immunoglobulin has a half-life in vivo
of around 25 days . The antibody-producing plasma
cells that develop during an immune response migrate to
the bone marrow, where they are very long lived. In addition,
there may be continuous regeneration of memory B cells in
contact with persisting antigen and helper T cells. Particulate
antigens persist for years in lymph nodes, held by follicular
dendritic cells . Antigen persistence and cross-reactive
antigens probably help to keep these B cells alive, dividing
occasionally and secreting antibodies.
It is remarkable that a mother can transfer sufficient
antibody to protect her infant when she was infected 20–30
years previously. The transmission of protective antibody pro-
tection from a mother to her child is hugely important,
especially in environments where 15% or more infants and chil-
dren die of infection. Paradoxically, a mother who avoided a
dangerous childhood infection, through herd immunity, may
actuallyput her child at risk by being unable to transfer specific
There are a large number of asymptomatic chronic infec-
tions, mostly viral, that provoke immune responses. Examples
are cytomegalo virus (CMV), Epstein– Barr virus (EBV) and
Mycobacterium tubercolosis (Mtb), but the full list is long and
expanding . EBV, CMV and Mtb provoke very strong CD4
and CD8 T-cell responses in humans. The CMV-specific
CD8 T-cell response can result in oligoclonal T-cell expansions
reaching more than 10% of circulating CD8 T cells. These
T cells are important because they control the virus
and their depletion, for instance by immunosuppressive
therapy, can activate the infection (e.g. Mtb,EBV,CMV),with
The evolution of antibody responses in B lymphocytes has
been reviewed elsewhere in detail . In brief, naive B cells
with antibody receptors specific for the immunogen bind anti-
gen in the germinal centre of lymph nodes and receive a partial
signal. The bound antigen is internalized and digested in lyso-
somes. A few resulting peptides bind to the HLA class II
molecules of that cell and are then presented on the cell surface
where T follicular helper cells with appropriate T-cell receptors
respond and deliver further signals, including IL-21, to the B
cell. These signals trigger B-cell division, class switching of
the antibody genes and somatic hypermutation. B cells that
express mutated antibody that binds immunogen with higher
affinity are then favoured. Selection for better binding
antibodies continues over months, ultimately resulting in
rspb.royalsocietypublishing.org Proc. R. Soc. B 282: 20143085
high-affinity antibody coming from highly mutated germ line
genes. High-affinity antibodies are more effective at neutraliz-
ing or opsonizing invading microbes and their pathogenic
The somatic hypermutation process does not occur in T cells,
even though they have antibody-like T-cell receptor genes,
because there is no advantage in having a high-affinity T-cell
receptor. The T-cell receptor binding to the peptide–HLA com-
plex on an antigen presenting cells has low affinity. It is enhanced
by several co-receptor– ligand pairs that are not antigen-specific,
giving the T cell the signal to divide and function.
As a result of an immune challenge, the responding T and B
cells may expand transiently to very high numbers , some-
times more than 10% of all circulating T cells, but these decline
rapidly as a result of activation-induced cell death and from
attrition over a longer time period. Thus as the pathogen is con-
trolled and disappears, some memory T and B cells persist for a
long time in numbers that far exceed the number of naive and
‘naive-memory’ T cells that were there before infection.
As the individual gets older, he or she develops an expand-
ing repertoire comprising memory T and B cells triggered by
previous infections and vaccinations, but also a naive-memory
repertoire shaped by exposure to the microbiome, food antigens
and inhaled antigens. Given the great complexity of the T- and
B-cell repertoires and a large stochastic element in choosing
which cells will respond to a given stimulus, and somatic
mutations in B cells, the precise composition will differ in each
individual, even in monozygotic twins . Add to this con-
siderable genetic variability in how individuals respond,
determined by the highly polymorphic HLA genes  and
by the genes of innate immunity, and it is not surprising that
the immune responses of any single adult vary considerably.
It is beyond the scope of this review to explore the immunology
of pregnancy in detail (reviewed in [68,69]). However, success-
ful reproduction is of central evolutionary importance and there
are immunological issues. How the newborn retains mechan-
isms by which the fetus minimizes its immune responses to
the mother has been discussed above. A bigger puzzle is how
the mother tolerates a semi-allogeneic graft without rejecting
it and without the immunosuppression necessary to accept an
organ transplant . There are features at the trophoblast
maternal interface at the site of initial implantation and in the
placenta that subvert the normal graft rejection immune
response. These include expression only of non-polymorphic
non-classical HLA antigens on the trophoblast , local
immune suppression mediated by infiltrating NK cells ,
monocytes and T regulatory cells [69,73], and inhibition of
T-cell activation by tryptophan catabolism . Around the
time of implantation, a local inflammatory response sets up
the stable placental site . There is evidence that the mother
changes the balance of her T-cell responses to Th2 rather than
Th1 . Thus pregnant women can show remissions of auto-
immune disease , and are more susceptible to severe
complications of influenza  and some other infections.
This immune modulation, necessary for the well-being of the
fetus, can occasionally be harmful to the mother.
(b) Malignancy and autoimmunity
The primary role of the immune system is probably to protect
against infections. Other roles such as destruction of mutated
cells may be very important, though more so in old age after
reproduction. Many tumours turn off T cells specific for
tumour antigens by binding to ‘check-point’ receptors such
as PD-1 or CTLA4, and new treatments that block these
receptor– ligand interactions have great therapeutic potential
[77,78]. However, the side effects of such therapy and of the
passive transfer of anti-cancer T cells include autoimmune
reactions, suggesting a balance between anti-self-immune
reactions preventing cancer and causing autoimmunity .
In adult life, the balance usually works, but one-third of
Western humans develop cancer, usually later in life, while
5–10% develop clinical autoimmune disease, so the balance
is finely set and may shift over time. The fading immune
system in old age (see below) may ameliorate autoimmunity
but at the expense of increased cancer risk.
Microorganisms cause about a quarter of all cancers (e.g.
EBV, hepatitis B and C viruses, human papilloma virus and
Helicobacter pylori). Specific T-cell responses normally hold
these microbes in check. However, if immunity is impaired
through ageing (see below), immunosuppressive therapy or
certain infections, particularly HIV-1, these cancers emerge .
Therefore, having developed a fully effective immune
response in early childhood, this matures as memory
accumulates and maintains the health of the individual
during critical periods of life, including child bearing. It not
only protects against potentially lethal infections but also
controls a number of persisting infections, some of which
have the potential to cause cancer. It can also deal with
mutant cells that have potential for becoming malignant. It
can be over-reactive and cause autoimmune disease or
allergy, a price paid for the overall benefit.
4. Immune decline with age
Last scene of all,
That ends this strange eventful history,
Is second childishness and mere oblivion,
Sans teeth, sans eyes, sans taste, sans everything.
As age advances, the immune system undergoes profound
remodelling and decline, with major impact on health and
survival [81,82]. This immune senescence predisposes older
adults to a higher risk of acute viral and bacterial infections.
Moreover, the mortality rates of these infections are three
times higher among elderly patients compared with younger
adult patients . Infectious diseases are still the fourth most
common cause of death among the elderly in the developed
world. Furthermore, aberrant immune responses in the aged
can exacerbate inflammation, possibly contributing to other
scourges of old age: cancer, cardiovascular disease, stroke,
Alzheimer’s disease and dementia .
During a regular influenza season, about 90% of the
excess deaths occur in people aged over 65. Furthermore,
poor immune responses account for diminished efficacy of
vaccines [82,85]. Immune senescence also results in reactiva-
tion of latent viruses, such as varicella-zoster virus, causing
shingles and chronic neuralgia.
Deterioration of the immune system with age may compro-
mise the homeostatic equilibrium between microbiota and host.
Thus reduced bacterial diversity in the gut has been correlated
with Clostridium difficile-associated diarrhoea, a major compli-
cation for the elderly in hospitals . Moreover, deviations
rspb.royalsocietypublishing.org Proc. R. Soc. B 282: 20143085
from the intestinal microbiota profile, which was established
in youth, are associated with inflammatory bowel disease
. The increase with age in pro-inflammatory pathobionts
and the decrease in immune-modulatory species may promote
and sustain inflammatory disorders .
At the same time, the ageing immune system fails to main-
tain full tolerance to self-antigens, with an increased incidence
of autoimmune diseases. . This is probably due to lympho-
paenia occurring with age, leading to excess homeostatic
lymphocyte proliferation , as well as a decrease in regulat-
ory T-cell function and decreased clearance of apoptotic cells
by macrophages .
Cancer is most frequent in older people; the median age for
cancer diagnosis in industrialized countries is approaching
70 years of age. The main reason is obviously the accumulation
of cellular and genetic damage throughout life; however, given
the role of the immune response in controlling cancers, reduced
immune functions in the elderly must contribute to the higher
risk . This immune impairment is in apparent contradiction
to the increase in autoimmunity as anti-tumour responses can
be directed against self; however, the general decline of the
immune system probably prevails and tumours are no longer
rejected as efficiently. Moreover, the increased inflammation
found with age facilitates cancer emergence.
The increased morbidity due to the decline of the immune
system is a directconsequence of dysregulated adaptive immunity
in the elderly. The low number of naive T cells versus T cells [41,42]
is a consequence of the reduced thymic output from the involuted
thymus. As a consequence of this age-induced lymphopaenia,
T cells proliferate andincrease the ‘virtual memory’ compartment
, but at the same time, the ability to establish immunological
memory in response to de novo antigens is reduced, compromis-
ing vaccinations. Functions such as cytokine production by CD4
kers is altered and the CD4
T-cell ratio is inverted
. The expanded T-cell responses that keep latent viruses such
as EBV and CMV under control reduces space for CD8
specific for other potentially lethal viruses , exacerbated by
the reduced thymic naive T-cell output.
While peripheral B-cell numbers do not decline with age,
the composition of this compartment changes. Similar to T
cells, naive B cells are replaced by antigen-experienced
memory cells, some of which are ‘exhausted’ (CD19
), and they display decreased affinity maturation and
isotype switching .
In general, the changes in the T- and B-cell compartments
hamper the adequate immune response to new acute and
latent viral infections and vaccinations.
The innate immune response also declines with age. There
are changes in innate cell numbers, with skewing of haemato-
poiesis towards the myeloid lineages [93,94]. The senescent
neutrophil is less functional with decreased phagocytic ability
and superoxide production partly due to decreased Fc
tor expression . Similarly, ageing macrophages have a
decreased respiratory burst. Together with DCs, they display
reduced phagocytic function and HLA II expression . The
immunological ‘silent’ removal of apoptotic and increasing
numbers of senescent cells is therefore compromised, and
may contribute to the pro-inflammatory phenotype. Indeed,
when senescent cells were removed from aged mice artificially,
the animals lived longer and were healthier .
Possibly the most critical change in the ageing innate
immune system is the increase in pro-inflammatory cytokines
IL-1b, IL-6, IL-18 and TNFa. The resulting low-grade
inflammation probably contributes to atherosclerosis, demen-
tia and cancer, inextricably linking inflammation and ageing
of other tissues [84,98].
The cellular and molecular basis of immune senescence is
still not well understood. Three phenotypes characterize
senescent cells: telomere attrition accompanying each round
of proliferation, leading to arrested cell division or ‘replicative
senescence’; increased mitochondrial load/dysfunction and
reactive oxygen species; and senescence-associated secretory
phenotype (SASP), defined as the secretion of pro-inflamma-
tory cytokines, chemokines and proteases by senescent cells
. While most of the data have been obtained in fibroblasts,
senescent immune cells probably show similar features.
These features impact on mitotically active cells by depletion
or arrested division (e.g. haematopoietic stem cells—HSCs or
T cells), and on post-mitotic immune cells by causing cellular
dysfunction (e.g. neutrophils).
Attrition of telomeres is a protective mechanism against
cancer, as each round of proliferation is likely to introduce
mutations . Only epithelial lymphocytes and stem cells
including haemopoietic (HSCs) express the telomere-lengthen-
ing enzyme telomerase in the adult , requiring a careful
balance against the risk of cancer. Both memory T cells and
HSCs characteristically divide rarely, to minimize telomere
attrition, but reliably either in response to infection (memory
lymphocytes) or for tissue renewal (stem cells) throughout the
entire lifespan. End-stage senescent CD27
have the shortest telomeres and show decreased proliferation
after activation, but nevertheless exhibit potent effector func-
tions. These cells accumulate in old age and in patients with
autoimmune diseases and chronic viral infections . The
second characteristic of aged cells is increased mitochondrial
dysfunction and ensuing oxidative damage to proteins and
DNA. DC function in aged micecan be restored through admin-
istration of anti-oxidants . Oxidative stress causes DNA
breaks and may be the cause of telomere attrition, which links
the first two causes of ageing. The accumulation of oxidative
damage could be due to a decline in lysosomal and autophagy
function . Autophagy, degrading bulk cytoplasmic material
by delivering it to the lysosomes, falls with age, including in
T cells . Mice without autophagy in their
haematopoietic system display a prematurely aged haemato-
poietic system . Failing memory T cells’ responses to flu
vaccination observed in the elderly can be restored with an
autophagy-inducing compound . A third more recent
addition to these fundamental changes of aged cells is the acqui-
sition of the SASP, contributing to increased pro-inflammatory
cytokine secretion and low-grade inflammation .
5. Evolution of the human immune system
As a long-lived species, humans have evolved mechanisms of
innate immunity and immunological memory to survive recur-
rent infections.However,over the lifetime of an individual, these
immune mechanisms change, first to adapt to the change from
fetus to infant, and then to mature and expand during growth,
subtly changing in pregnancy and finally decreasing in senes-
cence. The output of naive lymphoid cells and the ability to
form new immunological memory becomes increasingly less
important as the older individual will have encountered and
established a memory bank to many pathogens over its lifetime.
rspb.royalsocietypublishing.org Proc. R. Soc. B 282: 20143085
There is a possibility that the myeloid bias and the increased
secretion of pro-inflammatory cytokines during ageing are
essential for improved phagocytosis of an increasing number
of senescent cells, raising the question of whether the changes
in the ageing immune system might serve a purpose.
The immune system has been primarily moulded by evol-
ution to respond efficiently to acute infections in young
people, to adapt to pregnancy and to transmit protection to
infants, and is adapted to cope with many chronic infections
lasting for decades. Apart from fighting viruses, bacteria,
fungi and parasites, the immune system also assumes other
roles such as tissue repair, wound healing, elimination of dead
and cancer cells, and formation of the healthy gut micro-
biota. Assuming an absence of a major selective pressure on
humans beyond reproductive age, we may have to pay for gen-
etic traits selected to ensure early-life fitness by the later
development of immunological phenotypes such as chronic
inflammation. Massive ageing and advanced longevity are
very recent phenomena occurringin an optimized environment.
As proposed by Hayflick , ageing may be an artefact of
civilization, and hence changes in the ageing immune system
might just be a consequence of evolutionary unpredicted anti-
genic exposure over the lifetime of an individual.
In some aspects, the immune system of the aged organism
resembles that of the newborn, with reduced antimicrobial
activity by neutrophils and macrophages, reduced antigen pres-
entation by DCs and decreased NK killing, and somewhat
compromised adaptive lymphocyte responses. Both the very
young and old immune systems are therefore similarlycompro-
mised in coping with a typical viral infection such as influenza,
whereas the young (non-pregnant) adult organism seems to be
perfectlyequipped for this challenge (figure 1). The evolution of
the immune system within an individual possibly reflects the
central role of the young adult in the survival of the species
for its procreative potential.
Competing interests. We declare we have no competing interests.
Funding. A.K.S. was funded by a Wellcome Trust New Investigator
Award and G.A.H. by Wellcome Trust Strategic Awards.
Acknowledgements. We acknowledge Andrew Allen for preparation of
All epigraphs in this paper are from William Shakespeare’s As you
like it, act 2, scene 7.
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