CD8 T cell clonal expansions & aging: A heterogeneous phenomenon with a common outcome

Abstract

A highly diverse CD8 T cell repertoire is thought to be critical for maintaining appropriate immune defenses against a variety of pathogens. However, in many aged individuals, the diversity of T cell receptors is significantly reduced by the presence of large, monoclonal expansions of CD8 memory T cells. While ongoing research is focused on understanding the molecular alterations in these expansions, one major hurdle to this goal is the apparent heterogeneity of CD8 clonal expansions, which is apparent even in reductionist systems. In this review, we discuss current evidence that CD8 clonal expansions are a heterogeneous phenomenon, and our evolving understanding of what this heterogeneity tells us about CD8 memory T cell homeostasis and how it is altered in aged individuals. The phenomenon of CD8 clonal expansionsIn healthy, young individuals, the repertoire of antigen receptors (T cell receptors, TCRs) on CD8 T cells is highly diverse, with no single TCR dominating the repertoire. With increasing age, however, one common change to the TCR repertoire is the development of CD8 T cell expansions, in which a single clone of CD8 T cells, bearing a single TCR, occupies a significant proportion of the total CD8 T cell pool.CD8 T cell clonal expansions are a common age-dependent alteration, affecting about onethird of humans over the age of 65, and almost 60% of mice over the age of 2 years (Ku et al., 1997;Ricalton et al., 1998). While this phenomenon is common, the magnitude of CD8 clonal expansions can vary widely. In the most dramatic cases found in inbred mice, a CD8 clonal expansion (i.e. a single CD8 T cell specificity) can occupy 90% of the CD8 T cell repertoire (unpublished data), whereas in humans, CD8 clonal expansions can occupy up to 50% of the CD8 T cell repertoire.

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

“…In aged individuals, CD8 + T cells undergo large clonal expansions of particular TCR Vβ repertoires (Clambey et al ., 2007). In agreement with prior work, CD8 + T cells from some aged mice showed clonal T‐cell expansions (Fig.…”

Human cytomegalovirus-specific CD8+ T-cell expansions contain long-lived cells that retain functional capacity in both young and elderly subjects

“…Such Vb expansions may also be found in young subjects, suggesting that it is not just chronology that drives their accumulation. 17 What is not known, however, is the mechanism by which these HCMV-specific populations become so large. Two alternative models may be considered, one depending on proliferation, the other on accumulation.…”

Cell-Intrinsic Defects in the Proliferative Response of Antiviral Memory CD8 T Cells in Aged Mice upon Secondary Infection

“…Changes also occur in both B and T cell responses during aging (15). These changes include a global shift from naive to memory-phenotype T cells resulting in a decrease in the number of naive T cells and an increase in T cells of memory phenotype (16)(17)(18)(19), clonal expansions of memoryphenotype T cells in mice, primates, and humans (18,(20)(21)(22), and changes in regulatory T cell (Treg) numbers (23,24). Although new thymic emigrants in aged mice appear more functional than their counterparts that have aged in the periphery (25), the dramatic decrease in thymic output with age leads to a reduced peripheral naive CD4 and CD8 T cell pool with age.…”