Two compensatory pathways maintain long-term stability and diversity in CD8 T cell memory repertoires

The time-dependent changes of human memory T cell repertoires are still poorly understood. We define a T cell memory repertoire as the pool of clonotypic lineages participating in a recall response to the influenza M1(58-66) epitope. In HLA-A2 individuals, this response predominantly uses BV19 chains with Arg-Ser (RS) in the CDR3 loop. We previously showed that the repertoire is polyclonal with a large fraction of clonotype that are only observed once. In this study, we perform longitudinal analyses of memory repertoires in three middle-aged individuals at times that spanned from 7 to 10 years. In these individuals, who are well into thymic involution, a substantial number of clonotypes were stable, e.g., detected at two times. The shape of the repertoire was stable over time as reflected by a number of repertoire characteristics, including singletons, i.e., the fraction of clonotypes observed only once, and repertoire diversity. However, the RS-clonotype subset showed a significant decline in the fraction of singletons and in clonotypic diversity. Thus, repertoire structure is maintained over time by a recruitment of non-RS-clonotypes and a shift of existing RS-clonotypes into higher frequencies. The recruitment of new clonotypes into the low-frequency component of the repertoire implies a role for these clonotypes.