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

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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.

Section snippets

The phenomenon of CD8 clonal expansions

In 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

Impact of CD8 clonal expansions on immune function and health

By using the above criteria, CD8 clonal expansions are large, monoclonal outgrowths of memory CD8 T cells in aged, healthy individuals. Although CD8 clonal expansions meet some criteria that are common to tumors (e.g. clonality and increased competitive advantage relative to their neighbors), CD8 clonal expansions are clearly not tumors. First, individuals with expansions have no change in the total number of CD8 T cells (Messaoudi et al., 2004). Second, individuals (both humans and mice) live

Factors that promote the development of CD8 clonal expansions

There are three factors that have been associated with an increased risk for the development of CD8 clonal expansions: age, lymphopenic conditions, and infection with cytomegalovirus. The best defined of these criteria is age. There is a clear age-dependent increase in the incidence of CD8 clonal expansions, and in general, young, healthy individuals with CD8 clonal expansions are rare (Callahan et al., 1993, Ricalton et al., 1998). While chronological age clearly increases the risk of

Altered properties of CD8 clonal expansions

Given the unusual accumulation of CD8 T cells in clonal expansions, research has focused on the biological properties of, and molecular alterations within, CD8 clonal expansions. In particular, studies of mice have provided new insight into unusual properties of CD8 clonal expansions. First, many CD8 clonal expansions have an increased rate of basal proliferation compared to normal CD8 memory T cells, with CD8 clonal expansions dividing once every 15 days in contrast to normal CD8 memory T cells

Heterogeneity among CD8 clonal expansions

Although CD8 clonal expansions clearly have altered biological properties, the molecular basis of these changes remain poorly defined. One significant challenge to elucidating the molecular basis of clonal expansions is the apparent heterogeneity of this phenomenon. CD8 clonal expansions are heterogeneous by at least three criteria.

(i) CD8 clonal expansions appear to have different requirements for antigen. On one hand, some expansions appear to be relatively antigen-independent. This is best

New insights into the heterogeneity of CD8 clonal expansions

To elucidate the molecular alterations in CD8 clonal expansions, we previously performed microarray analysis of CD8 clonal expansions (manuscript in preparation). In this analysis, we purified both CD8 clonal expansions as well as age-matched polyclonal, CD8 memory T cells from the same mice. After performing microarray analysis, we identified a number of genes whose expression was different between CD8 clonal expansions and polyclonal CD8 memory T cells. One of these alterations was in

Acknowledgments

This work was funded by USPHS Grants AI-8785, AI-17134, AI-22295, and AI-52225. ETC is a recipient of a National Research Service Award from the National Institutes of Health. We thank Dr. C.-C. Ku for providing unpublished data, and Dr. Linda van Dyk for critical reading of the manuscript.

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