Private specificities of CD8 T cell responses control patterns of heterologous immunity

Kim, Sung-Kwon; Cornberg, Markus; Wang, Xiaoting Z.; Chen, Hong D.; Selin, Liisa K.; Welsh, Raymond M.

Here, we have documented that a host's unique private specificities of its viral epitope-specific memory T cell population can determine the cross-reactivity patterns to subsequent heterologous virus infections. It shows that these unique private specificities, rather than being meaningless immunological curiosities, impact the recognition of crossreactive antigens encoded by other pathogens and, as a consequence, have the potential to alter the pathogenesis of a viral infection in a manner that is unique to the individual. This work was initially based on the puzzling observation that, unlike LCMV-infected mice challenged with PV, where a clearly defined cross-reactive epitope-specific CD8 T cell response predictably dominates, VV infection of LCMV-immune mice elicits a more subtle and less predictable expansion of LCMV epitope-specific CD8 T cells (3, 4) . Here, we used sensitive measures to analyze these less predictable responses and have revealed new insights into the complexities of T cell dynamics during virus infections. Longitudinal analyses of LCMV-immune mice before and after VV infection revealed that, although many of the LCMVspecific memory cells were profoundly reduced in frequency, others, presumably cross-reactive T cells specific to distinct epitopes, were either maintained or increased in frequency (Fig. 1) . Attrition of noncross-reactive CD8 T cells after VV infection probably resulted from cytokine-induced bystander apoptosis of memory cells, shown to occur during viral infections (21) (22) (23) . Fig. 1 D shows that cells of all specificities decline at day 4 after infection and T cells specific to only some, presumably cross-reactive, peptides thereafter increase in number. Of note is that there was considerable variation between mice regarding what group of epitopespecific T cells was stimulated by VV. This mouse-to-mouse variation in epitope selectivity was also seen in measure-ments of the down-regulation of IL-7R␣, an indicator of recent TCR stimulation (Fig. 2 ) and in loss of CSFE label studies, an indicator of T cell proliferation (Fig. 3) .