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
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.
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