Aspects of immunosenescence

age-related factors affecting primary CD4+, CD8+ T-cell responses and memory T-cell

Age-related declines in immune function render the aged more susceptible to opportunistic infections, chronic diseases, incidence of cancer and less able to generate protective immune response to vaccination.

T-cell memory generated during youth generally functions well into old age.

whereas immune memory generated later in elderly functions poorly.

CD4+T cell immunosenescence

Intrinsic changes of aged naive CD4+T cells limit the initial priming event in activation, expansion and differentiation.

Age-related declines in CD4+ T-cell are in Size and Function.

Reduced T-cell receptor signaling Intensity doe to:

It has been demonstrated that naive CD4+ T cells from aged mice do not form immunologic synapses as efficiently as do cells from young mice.

Reduction of 50% in recruitment of signaling molecules (e.g. Lck, ZAP-70, Fyn, LAT, Grb2 and Vav) to these synapses in aged CD4+ T cells compared with young cells.

Significant alterations in cell surface glycosylation and phosphorylation of key signaling molecules.

long life and chronic antigenic load may represent the major driving force for immunosenescence, by reducing the number of naïve, results in their replacement by expanded clones of antigen-specific effector and memory T cells which display a late and differentiation phenotype.

Defects in expansion after stimulation, as naive CD4+T cells from young mice expanded 12-fold, whereas those from aged mice only expanded 5-fold.

Aged CD4+ effectors cells do up regulate expression of CD62L and decrease surface CD25 expression.

Reduced production of IL-2, aged mice have been shown to produce less IL-2 and expand poorly after stimulation compared with their young counterparts.

*The defective expansion and differentiation of aged naive cells during effectors generation could be reversed by the addition of exogenous IL-2, indicating they are defective in IL-2 production but not responsiveness.

what is the underlying cause of these defects?

thymic involution

The most important factor contributing to the onset of immunosenescence is thymic involution that in mammals.

The thymus and human immune system are generally believed to have evolved to last 40–50 years. the average lifespan is now twice that at ~ 80 years.

Attempts to find a rationale- make room for memory cells.- thymus is simply no longer needed during adult

life because T cells are long-lived. - thymus is a ‘disposable soma’, and it involution

with age represents conservation and redirection of energy.

- necessary to avoid autoimmunity. role in the maturation of the immune system by allowing a type of selection to occur in the periphery that produces an optimal repertoire of naive T cells during young-adult life.

thymic function gradually starts to decrease from the first year of life.

The true thymic epithelial space begins to involutes shortly after birth and decreases ~ 3%/yr through middle age (35–45) years of age and continues to decrease ~1%/yr throughout the rest of life.

In mice, increased frequencies of apoptotic triple-negative CD3¯CD4¯CD8¯ T cells are found.

A study demonstrated in mice that the number of recent thymic emigrants in the periphery peaks at 6 weeks of age and declines thereafter.

both thymus weight and number of thymocytes significantly decreased with age.

This decrease was detectable by as early as 12 weeks of age, compared with thymus at age 6 weeks.

* CD4 and CD8 flow cytometric analyses of freshly isolated thymocytes from young (3 days) and aged (78 years) healthy donors.

* (PBMC) peripheral blood mononuclear cell.

- change expression patterns of cytokines. As thymic epithelial cells can produce several hematopoietic cytokines such as G-CSF, GM-CSF, IL-1, IL-3, IL-6, IL-7, macrophage-colony stimulating factor (M-CSF), stem cell factor (SCF), transforming growth factor b (TGF-b), oncostatin M (OSM), and leukemia inhibitory (LIF).

profiled cytokine mRNA levels in 45 normal human thymus tissues (aged 3 days to 78 years) data shows:

IL-6 family mRNAs were expressed significantly higher in aged human thymus (IL-6 induce rapid and acute thymus gland involution and decreased thymic export to the periphery).

mRNA levels of IL-7, a potent cytokine for thymopoiesis, remained constant in the aged human thymus.

This suggested that loss of thymo-stimulatory factor e.g. IL-7 expression alone is not mechanistically sufficient for age-induced thymic involution.

the role of thymic involution which results in a diminished quantity and quality of thymocytes exported over time. in the acquisition of age-related declines in CD4+ T-cell less efficient development and function ability to respond to stimulation.

evident when young mice are Thymectomized, CD4+ T cells possessed significant defects in IL-2 production and CD25 expression following stimulation with peptide pulsed APC.

The resident cells have increased longevity to compensate for reduced output.

BUT Several studies support the hypothesis that

increased post-thymic longevity of CD4+T cells in the periphery is sufficient for the accumulation of functional defects in CD4+T cells in older individuals impact on their ability to respond to stimulation.

Some studies that new CD4+ T cells generated from aged bone marrow stem cells in young hosts are highly functional, responses in both primary and memory and function well to help humeral responses.

Thus, even though aged bone marrow remain functional, the aged thymus microenvironment plays an important role in producing defective T cells.

Age-related declines in T-cell repertoire diversity.

The generation of T-cell receptor diversity is entirely dependent on the production of new T cells by the thymus yet, the output of new T cells is severely reduced by thymic involution.

Age-related declines T-cell repertoire diversity provides an explanation for the increased susceptibility to infectious disease & reduced vaccine efficacy.

Impact of progressive aging on CD8+ T-cell responses

Decline in responsiveness to newly encountered antigens.

Age-related declines in CD8+ T-cell repertoire diversity.

Nonmalignant expansion of individual CD8+ T-cell clones. poor generation of CD8+ T-cell memory.

data suggest that the age-related impairment of CD8+ lymphocyte activity during a primary infection is due to a defect in the expansion, rather than in effectors activity of specific CD8+ T cells.

Decline in responsiveness to newly encountered antigens

Aged mice exhibit a lower percentage of specific CD8+T cells after infection and delay in the peak of the CD8+ T-cell response compared with young counterparts.

Aged mice exhibited a five fold reduction in the CD8 T-cell response.

The frequency of CD8+ T cells capable of producing IFN-γ in response to antigenic peptides was reduced in aged mice.

Age-related declines in CD8+ T-cell repertoire diversity

Homeostatic proliferation is able to maintain the number of peripheral naive T cells in aged mice, the overall T-cell repertoire diversity is compromised through the selective outgrowth as the maintenance of individual T-cell clones differs based on TCR avidity.

Nonmalignant expansion of individual CD8+ T-cell clones T-cell cloneal expansions can dominate as much

as 50% of the peripheral CD8+ T-cell repertoire in aged humans and up to 80% of the repertoire in aged mice.

Most T-cell cloneal expansions identified in mice and humans are believed to arise from the dys-regulated outgrowth of T-cell clones in response to persistent antigenic stimulation during chronic infections.

Although these cells are nonmalignant, they are functionally impaired.

T-cell cloneal expansions severely compromises the overall size and diversity of the T-cell pool, reducing responsiveness to newly encountered pathogens.

T cell immunosenescence, possibly, mortality and morbidity will occur earlier in people that have been exposed to an antigenic overload (due to chronic infections).

A recent report showed that antigen-specific T-cell cloneal expansions can also develop from the pool of conventional memory CD8+ T cells generated after infection.

These cells can be considered part of the memory T-cell pool, because they retain the ability to respond to antigen

Impaired generation of CD8+ T-cell memory

robust and long-lasting memory CD8+ T cells are not generated after infection of aged mice.

even if an adequate primary response to infection is generated, CD8 memory generation is deficient.

The mechanisms underlying this are not well characterized and might be a consequence of several factors.

- poor CD4+ T help - impaired function and reduced diversity in the

CD8+T-cell repertoire.

CD4 + and CD8+ T-cell memory generated when young is maintained for long term and remains functional.

However, there are significant changes in the nature of peripheral and systemic memory over time. E.g. after a respiratory virus infection, the number of memory cells in the airways (peripheral memory) declines, whereas the numbers of memory cells in the spleen (systemic memory) remain stable over time.

age-associated dysregulation of apoptosis could account for the accumulation of dysfunctional CD8+ cells.

In contrast, CD4+ cells seem to become increasingly susceptible to apoptosis with age, in vitro.

CD28¯ T cells: their role in the age-associated decline of immune function

The accumulation of CD¯28 T cells, particularly within the CD8 subset, is one of the most prominent changes associated with aging in humans.

CD28, major co-stimulatory receptor, is responsible for the optimal antigen-mediated T-cell activation, proliferation and survival of T cells.

CD¯28 T cells arise from CD28+ naive and memory T cells that have undergone repeated stimulation by antigen and/or by cytokines, particularly homeostatic cytokines IL-2, IL-7, IL-15.

significant decrease of CD28 expression by CD8 cells of old compared to middle-aged individuals.

old memory cells, i.e. CD8 cells that have encountered the antigen and have been chronically stimulated over time, tend to lose CD28 and, as a result, multiply less robustly when exposed to antigens than do younger cells.

At birth, all human T cells express CD28; however, by age 80 and above, 10–15% CD4 and 50–60% of CD8 T cells lack CD28 expression.

CD¯28 T cells exhibit - defective antigen induced proliferation- reduced antigen receptor diversity- enhanced cytotoxicity and regulatory

functions, reducing overall immune response to pathogens and vaccines in the elderly.

- decreased ability to secrete IL-2 after activation.

B cells and aging: molecules and mechanisms

B cells and aging: molecules and mechanisms

B cells play central roles in the establishment and maintenance of protective immunity, including the generation of protective antibodies, antigen presentation, and more recently, appreciated regulatory functions.

Age associated changes in behavior and production :

- reductions in precursors capable of generating B cells. (smaller pre-B pools)

- reductions in the functional potential of B cells.and - shifts in the diversity in repertoire.

age descriptive studies have revealed central changes in HSCs and developing B-cell subsets play a role in shifting the sizes and functional potential quality of BM B-cell output.

In vivo studies confirm two to five fold reductions in mature B-cell in aged individuals.

- HSC intrinsic changes. - the frequency of precursors capable of generating B

cells in vitro is reduced (smaller pre-B and immature BM pools).

- down regulation of genes that mediate lymphoid specification and function

- Reduced BCR diversity- Poor responses to vaccination and new infections.- Poor memory responses

Changes are required interplay between intrinsic and micro-environmental signals.

E.g. BM stromal cells from aged mice provide less IL-7, but B-cell progenitors from aged mice also respond less efficiently to IL-7.

The levels of gene products vital to lineage commitment and subsequent differentiation are altered in aged.

- the expression of transcriptional regulators essential to generating pro-B cells, including E2A gene products are reduced. (decreased E2A levels directly compromise lineage specification and developmental progression).

- E2A - regulated AID - are reduced producing secondary antibody responses lacking characteristic class switched, hyper-mutated antibodies.

- the expression of genes crucial to passage through the pro- and pre-B cell stages, including RAG enzymes and lambda-5, is diminished in developing B cells from aged individual.

in the adult BM, include the predominant B2 cell pathway, a second pathway devoted to the B1 cell lineage these two developmental pathways vary with age.

B1 cells predominate in peritoneal and represent a self-

renewing pool that is established early in life. B1 cells express a specificity repertoire that is generally characterized by low-affinity (natural antibodies).

B2 production wanes with age, the proportional contribution of the B1 pathway again increases.

The exact consequences of this reversion in the proportional representation of B1 versus B2 output remain unclear but might contribute to some repertoire differences observed with advancing age.

pro-B cells in old mice are weaken in their capacity to rearrange the D to J gene segments and the V to DJ gene segments.

CDR3 analysis, has demonstrated significant loss of diversity in the peripheral blood of some aged ind. correlated with poor health and survival.

Age-related changes in the behavior of antigen experienced B cells (recently activated B cells, memory B cells and antibody-forming plasma cells) evidenced by diminished responses to infection or vaccination, as well as declines in existing humoral immunity.

it involves changes intrinsic to B cells and the accessory cells that must act to generate immune memory.

It is well established that germinal center formation are impaired; fewer GCs and smaller GC size in aged mice.

Antibody affinity maturation, memory B-cell differentiation, and long-lived plasma cells in BM are correspondingly reduced.

Interestingly, the mucosal system of aged mice might be functionally intact, because germinal center in Peyer’s patches of aged mice are similar in phenotype and occurrence to those of younger mice.

the capacity for cognate T-cell help is decreased, possibly reflecting reduced CD40 ligand expression, and contribute to the diminished efficacy of humoral responses.

follicular dendritic cells from aged mice are less effective at antigen trapping. The underlying mechanism in part reflects down regulated Fc receptors.

THE END