Age-related modifications of the human αβ T cell repertoire due to different clonal expansions in the CD4+ and CD8+ subsets

We have studied the effects of a life-long antigen stimulation on the clonal heterogeneity of human peripheral T cell subsets, as defined by their CD45 isoform expression. CD4(+) or CD8(+) T cells were obtained from healthy donors ranging in age from 20 to 100 years, and sorted into CD45RA(+) and CD45RO(+) populations. A modified PCR-heteroduplex analysis was then used to directly compare the TCR Vp clonal make up of either compartment pair. We find that the CD4(+) T cell repertoire remains largely polyclonal throughout life, since CD4(+) expanded clones are rare and accumulate predominantly in the CD45RO(+) compartment of exceptionally old donors (100 years old). In contrast, the CD8(+) T cell subset contains expanded clones which are already detectable in young adults and become very frequent in 70- to 75-year-old donors in both CD45RA(+) and CD45RO(+) compartments analyzed. Interestingly, some expanded clones are detectable in the CD45RA(+) or in both CD45RA(+) and CD45RO(+) compartments of either CD4(+) or CD8(+) T cells. These results indicate that the age-dependent accumulation of expanded clones starts earlier and is more pronounced in the CD8(+) than in the CD4(+) T cell subset, reinforcing the concept that clonal expansion in the two subsets is controlled by substantially different mechanisms. Furthermore, whereas the finding of expanded CD45RO(+) T cell clones is explained by antigen-driven proliferation, the detection of expanded clones in the CD45RA(+) or in both CD45RA(+) and CD45RO(+) compartments would support the hypothesis of reversion from the CD45RO(+) to the CD45RA(+) phenotype after antigen encounter.