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April 2011

Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation.

Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (T(regs)), a CD4(+) T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all T(regs), especially in aged hosts, we characterized T(regs) by the expression of FOXP3, a transcription factor crucial for T(reg) differentiation and function. The proportion of FOXP3(+)CD4(+) T(regs) increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3(+) T(regs) from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral T(regs) from elderly humans improves effector T cell responses in most subjects. Importantly, T(regs) from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young T(regs). The increased proportion of T(regs) in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old T(regs) efficiently suppressed the production of IFN-gamma by effector T cells. Finally, in vivo depletion of T(regs) in old mice attenuated disease severity. Accumulation of functional T(regs) in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of T(reg) numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population.

J Immunol. 2008 Aug 1;181(3):1835-48

The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age.

Ageing is associated with evidence of immune deficiency and dysregulation. Key changes in the immune system with ageing include a progressive reduction in naive T cell output associated with thymic involution and peripheral expansion of oligoclonal memory T cells. These features are associated with evidence of impaired immune responsiveness both in vitro and in vivo, termed immune senescence. CD4+ CD25+ T cells have recently been recognized as mediators of peripheral immune regulation and play a role in the control of autoimmune and pathogen-specific immune responses. The significance of CD4+ CD25+ regulatory T cells in the context of immunosenescence is not known. We have investigated the number, phenotype and function of CD4+ CD25+ T cells in healthy volunteers over a wide age range. We demonstrate that the number of CD4+ CD25+ and CD4+ CD25high T cells in healthy volunteers increases with age. In both age groups CD4+ CD25+ T cells showed a phenotype consistent with that described for regulatory T cells. Further analysis of CD4+ CD25high T cells in young and elderly donors showed equivalent expression of intracellular CTLA-4 and surface expression of activation markers. In vitro, functional titration assays of CD4+ CD25high T cells demonstrated equivalent regulatory function in both young and elderly donors, with suppression of proliferation and cytokine production in response to polyclonal T cell stimulation. These observations demonstrate an increase in peripheral blood CD4+ CD25high regulatory T cells associated with ageing. The relevance of these expanded cells in relation to the immune senescence seen in the elderly as yet remains unclear.

Clin Exp Immunol. 2005 Jun;140(3):540-6

Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging.

Clinical observations indicate that elderly people are prone to severe, often lethal infectious diseases induced by novel pathogens. Since the ability to mount primary immune responses relies on the availability of naive T cells, the circulating naive T-cell reservoir was evaluated throughout the human life span. Naive T cells were identified as CD95(-) T lymphocytes for their phenotypic and functional features. Indeed, the lack of CD95 marker is sufficient to identify a population of naive T cells, as defined by coincidence with previously characterized CD45RA(+) CD62L(+) T cells. Naive CD95(-) T cells, as expected, require a costimulatory signal, such as CD28, to optimally proliferate after anti-CD3 stimulation. Cytofluorimetric analysis of circulating T lymphocytes from 120 healthy subjects ranging in age from 18 to 105 years revealed that naive T cells decreased sharply with age. The younger subjects had a naive T-lymphocyte count of 825 +/- 48 cells/microL, and the centenarians had a naive T-lymphocyte count of 177 +/- 28 cells/microL. Surprisingly, the naive T-cell count was lower in CD8(+) than in CD4(+) subsets at any age, and the oldest individuals were almost completely depleted of circulating naive CD8(+) T cells (13 +/- 4 cells/microL). Concomitantly, a progressive expansion of CD28(-) T cells occurs with age, which can be interpreted as a compensatory mechanism. These data provide new insights into age-related T-cell-mediated immunodeficiency and reveal some analogies of T-cell dynamics between advanced aging and human immunodeficiency virus (HIV) infection. In conclusion, the exhaustion of the naive CD8(+) T-cell reservoir, which has never been reported before, suggests that this T-cell pool is a major target of the aging process and may define a parameter possibly related to the life span of humans.

Blood. 2000 May 1;95(9):2860-8

Immunological studies of aging. Decreased production of and response to T cell growth factor by lymphocytes from aged humans.

Human lymphocytes from elderly and young donors were cultured with phytohemagglutinin (PHA) or concanavalin A. Cultures from old donors produced less T cell growth factor (TCGF) and incorporated less tritiated thymidine (3H-Tdr) than did similar cultures from young donors in the presence of either mitogen. Furthermore, the response of lymphocytes from elderly donors to TCGF was impaired. Thus, PHA-activated T cells from aged donors showed no increase tritiated thymidine incorporation when incubated with exogenous human TCGF. In contrast, addition of exogenous human TCGF to PHA-activated peripheral blood leukocytes from younger individuals increased tritiated thymidine incorporation by 30-50%. The impaired response to TCGF was associated with decreased binding of TCGF by PHA-activated cells from old donors. TCGF production or responsiveness was not associated with the presence of “suppressor” activity in elderly T cell preparations. These studies suggest a possible molecular mechanism for the impaired proliferative response of elderly human T cells. These data lend support to the hypothesis that defects in the capacity to either produce or respond to TCGF may be a fundamental cause of immune deficiency.

J Clin Invest. 1981 Apr;67(4):937-42

Homeostasis and the age-associated defect of CD4 T cells.

Survival and homeostatic division of naive CD4 T cells is regulated by the cellular and non-cellular milieu and together these processes ensure that a population of naive CD4 T cells persists into old age. However, the naive CD4 T cells from aged animals show reduced IL-2 production, proliferation, helper function and effector generation and memory function. We explore here whether the age-related defects in naive CD4 T cells are due to the aged environment from which they come or to intrinsic defects that are caused by homeostasis and their long lifespan.

Semin Immunol. 2005 Oct;17(5):370-7

Age-associated decline in effective immune synapse formation of CD4(+) T cells is reversed by vitamin E supplementation.

Aging is associated with reduced IL-2 production and T cell proliferation. Vitamin E supplementation, in aged animals and humans, increases cell division and IL-2 production by naive T cells. The immune synapse forms at the site of contact between a T cell and an APC and participates in T cell activation. We evaluated whether vitamin E affects the redistribution of signaling proteins to the immune synapse. Purified CD4(+) T cells, from the spleens of young and old mice, were treated with vitamin E before stimulation with a surrogate APC expressing anti-CD3. Using confocal fluorescent microscopy, we observed that CD4(+) T cells from old mice were significantly less likely to recruit signaling proteins to the immune synapse than cells from young mice. Vitamin E increased the percentage of old CD4(+) T cells capable of forming an effective immune synapse. Similar results were found following in vivo supplementation with vitamin E. When compared with memory cells, naive T cells from aged mice were more defective in immune synapse formation and were more responsive to vitamin E supplementation. These data show, for the first time, that vitamin E significantly improves age-related early T cell signaling events in naive CD4(+) T cells.

J Immunol. 2007 Feb 1;178(3):1443-9

The ageing immune system: is it ever too old to become young again?

Ageing is accompanied by a decline in the function of the immune system, which increases susceptibility to infections and can decrease the quality of life. The ability to rejuvenate the ageing immune system would therefore be beneficial for elderly individuals and would decrease health-care costs for society. But is the immune system ever too old to become young again? We review here the promise of various approaches to rejuvenate the function of the immune system in the rapidly growing ageing population.

Nat Rev Immunol. 2009 Jan;9(1):57-62

Decreased TNF-alpha synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4+ T cells during aging.

Immunity declines during aging, however the mechanisms involved in this decline are not known. In this study, we show that cutaneous delayed type hypersensitivity (DTH) responses to recall antigens are significantly decreased in older individuals. However, this is not related to CC chemokine receptor 4, cutaneous lymphocyte-associated antigen, or CD11a expression by CD4(+) T cells or their physical capacity for migration. Instead, there is defective activation of dermal blood vessels in older subject that results from decreased TNF-alpha secretion by macrophages. This prevents memory T cell entry into the skin after antigen challenge. However, isolated cutaneous macrophages from these subjects can be induced to secrete TNF-alpha after stimulation with Toll-like receptor (TLR) 1/2 or TLR 4 ligands in vitro, indicating that the defect is reversible. The decreased conditioning of tissue microenvironments by macrophage-derived cytokines may therefore lead to defective immunosurveillance by memory T cells. This may be a predisposing factor for the development of malignancy and infection in the skin during aging.

J Exp Med. 2009 Aug 31;206(9):1929-40.

Immunosenescence and cancer.

Age is a major risk factor for many cancers. Although this is usually viewed in the context of the cell biology, we argue here that age-associated changes to immunity may also contribute to the age-associated increasing incidence of most cancers. This is because cancers are immunogenic (at least initially), and the immune system can and does protect against tumourigenesis. However, immune competence tends to decrease with age, a phenomenon loosely termed “immunosenescence”, implying that decreased immunosurveillance against cancer could also contribute to increased disease in the elderly. This review weighs some of the evidence for and against this possibility.

Crit Rev Oncol Hematol. 2010 Aug;75(2):165-72

Mechanisms of immunosenescence.

On April 7,8, 2009 a Symposium entitled “Pathophysiology of Successful and Unsuccessful Ageing” took place in Palermo, Italy. Here, the lectures of G. Pawelec, D. Dunn-Walters and. G. Colonna-Romano on T and B immunosenescence are summarized. In the elderly, many alterations of both innate and acquired immunity have been described. Alterations to the immune system in the older person are generally viewed as a deterioration of immunity, leading to the use of the catch-all term immunosenescence. Indeed, many immunological parameters are often markedly different in elderly compared to young people, and some, mostly circumstantial, evidence suggests that retained function of both innate and acquired immunity in the elderly is correlated with health status. What is often not clear from studies is how far immune dysfunction is a cause or an effect. A better understanding of immunosenescence and mechanisms responsible for proven deleterious changes is needed to maintain a healthy state in later life and to design possible therapeutic interventions.

Immun Ageing. 2009 Jul 22;6:10

Ageing and the immune system.

Immune system alterations during ageing are complex and pleiotropic, suggestive of remodelling or altered regulation, rather than simple immune deficiency. The most dramatic changes with age occur within the T cell compartment, the arm of the immune system that protects against pathogens and tumours, consistent with the increased incidence and severity of infection and cancer in the elderly. Indeed, autopsy studies confirm infection as the major cause of death in the very old. Increased serum levels of inflammatory mediators are another hallmark of ageing, suggestive of either regulatory defects or an ongoing attack on sub-clinical neoplastic disease or infection. Qualitative changes in antibody production, including those secreted by the gut mucosal immune compartment, affect responses to foreign antigens as well as to prophylactic vaccines. Innate immunity, the first line of defence that precedes the antigen-specific T and B cell responses, also undergoes changes with age. Some of the immune effects associated with ageing are secondary to overall organismic changes, such as alterations in the viscosity of cell membranes and proteolytic cellular machinery. Evidence suggesting that immune system changes may be involved in some major age-related pathologies, such as atherosclerosis and Alzheimer’s disease, will be discussed.

Novartis Found Symp. 2001;235:130-9