Accumulation of memory T cells from childhood to old age: Central and effector memory cells in CD4+ versus effector memory and terminally differentiated memory cells in CD8+ compartment

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Abstract

Memory T cells can be classified as central memory (TCM, CD45RAnegCCR7+), effector memory (TEM, CD45RAnegCCR7neg), and terminally differentiated cells (TTD, CD45RA+CCR7neg) with different homing and effector capacities. In 101 healthy subjects aged from 5 to 96 years, distinct dynamics were evidenced between circulating CD4+ and CD8+ T cell populations. Naive CD4+ and CD8+ T cells decreased linearly with age, CD8+ twice more rapidly. Memory cells outnumbered naive cells on average at 37.4 in the CD4+ and 29.5 years of age in the CD8+ pool. CD4+ TCM and TEM cells were positively correlated and increased linearly at a similar rate with age, while CD4+ TTD remained rare. CD8+ TEM and TTD accumulated linearly with age, while TCM increased only slightly, and each memory subset was negatively correlated to the two others. Almost all CD8+ TTD and some CD8+ TEM had lost CD28 expression. Despite different dynamics, each individual CD4+ naive and memory subset was correlated to the synonymous CD8+ subset. Half of the subjects aged 65 years or older were characterized by extremely reduced CD8+ naive and increased CD8+ TTD cell counts, which could indicate an acceleration of the decay of the immune system from this age onward.

Introduction

With normal aging, the slow turnover and long lifespan of naive T cells are preserved (Wallace et al., 2004), but thymus output gradually declines, and ultimately becomes insufficient to replace naive T cells lost from the periphery and to maintain the breadth of the T cell repertoire (Kohler et al., 2005, Naylor et al., 2005). Conversely, cumulative exposure to foreign pathogens and environmental antigens induces the accumulation of memory T cells with age. Recent studies indicate that the memory pool is composed of different subsets based on the expression of chemokine receptors, selectins, and costimulatory receptors. Two to three memory T cell subsets are now recognized under steady-state conditions (Sallusto et al., 1999). Central memory T cells (TCM) bear lymph-node homing receptors (the l-selectin, CD62-L, and the CC-chemokine receptor 7, CCR7) and the costimulatory receptors CD27 and CD28. In some, but not all cases, these cells display limited immediate effector function, especially in the CD4+ T cell pool, but can have extensive replicative responses to their specific antigen (Maus et al., 2004). Effector memory T cells (TEM) retain capacity for immediate effector function (i.e. secretion of a broad spectrum of cytokines and/or ex vivo cytotoxic activity) but lack CCR7 and are heterogeneous for CD62-L expression. Both TCM and TEM have down-regulated the CD45RA marker. A third subset expresses CD45RA as do naive cells, but neither CCR7 nor CD62L. Variously termed TEMRA, CD45RA+ memory, terminally differentiated (TTD), or persisting effectors, these highly differentiated cells have generally lost expression of CD27 and/or CD28 and accumulate with age in the CD8+ T cell compartment (reviewed in Pawelec et al., 2005). Accordingly, CD28 loss is considered the most consistent immunological marker of ageing (Effros et al., 1994, Gupta et al., 2004, Vallejo, 2005). CD4+CD45RA+CCR7neg or CD28neg cells have also been evidenced as a minor CD4+ T cell subset (Harari et al., 2004, Vallejo, 2005).

The effect of age on the composition of naive and memory T cells pools, defined as TCM, TEM and TTD according to their phenotypic signatures, has generally been investigated by comparing groups of middle-aged and elder individuals. To precise the relationship between loss of naive and gain of individual memory subsets, we analyzed age-related changes from childhood to old age comparatively in the CD4+ and the CD8+ compartment. To this end, four color flow cytometric analyses were performed on peripheral blood of 101 healthy donors ranging from 5 to 96 years of age.

Section snippets

Donors

EDTA-anticoagulated blood was obtained in accordance with local institutional ethics approval either from healthy members of this laboratory or as specimens taken in the course of pre-operative checkup before eye surgery or blood testing of volunteer marrow/blood stem cell donors. Subjects taking drugs that could affect the immune system or had a current or recent acute infection, a prior history of neoplasia, autoimmune disease, poorly controlled diabetes mellitus, or febrile illness were

Results

A complete set of phenotypic analyses was obtained from each of 101 donors from 5 to 96 years of age. The sex and age mix were nearly identical for all age groups. In the absence of significant difference by gender, even after separate analysis of each naive and memory subset, the data for all subjects were pooled according to their age group (Table 1). There was a progressive decrease in the absolute numbers of CD4+ and CD8+ T cells with age, but when considering their relative proportions, CD4

Discussion

In this steady-state study, it was observed that the pool sizes of circulating CD4 and CD8 lymphocytes decrease progressively throughout life, without mirroring their percentage; however, since in relative proportion CD4+ T cells increased marginally, while CD8+ T cells remained stable. Other have also observed a decrease of absolute counts with age, but changes in the respective proportions of CD4+ and CD8+ T cells could differ between studies (Bisset et al., 2004, Fagnoni et al., 2000,

Acknowledgements

We would like to thank Claudine Grutzmacher for technical assistance, and Steven Richebourg and Marion Rodrigue for collecting data. We also wish to thank all the donors and the physicians who addressed us the blood samples.

References (42)

  • E. Naumova et al.

    Immunological markers contributing to successful aging in Bulgarians

    Exp. Gerontol.

    (2004)
  • J.K. Northrop et al.

    CD8+ T-cell memory: only the good ones last

    Curr. Opin. Immunol.

    (2004)
  • B. Rocha et al.

    Towards a cellular definition of CD8+ T-cell memory: the role of CD4+ T-cell help in CD8+ T-cell responses

    Curr. Opin. Immunol.

    (2004)
  • P. Sansoni et al.

    Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians

    Blood

    (1993)
  • R.D. Semba et al.

    T cell subsets and mortality in older community-dwelling women

    Exp. Gerontol.

    (2005)
  • C. Spaulding et al.

    Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation

    Exp. Gerontol.

    (1999)
  • R. Vescovini et al.

    Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells

    Exp. Gerontol.

    (2004)
  • G. Almanzar et al.

    Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons

    J. Virol.

    (2005)
  • V. Appay et al.

    Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections

    Nat. Med.

    (2002)
  • L.R. Bisset et al.

    Reference values for peripheral blood lymphocyte phenotypes applicable to the healthy adult population in Switzerland

    Eur. J. Haematol.

    (2004)
  • T.J. Fry et al.

    The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance

    J. Immunol.

    (2005)
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