The TCR’s sensitivity to self-peptide–MHC dictates the ability of naïve CD8(+) T cells to respond to foreign antigens

The strength of self-peptide–major histocompatibility complex (MHC) recognition dictates naïve CD8(+) T cell homeostasis, but its effect on foreign antigen reactivity is controversial. As CD5 expression correlates with self-recognition, we studied CD5(lo) and CD5(hi) naïve CD8(+) T cells. Gene expression characteristics suggested CD5(hi) cells were better poised for reactivity and differentiation compared to the CD5(lo) population, and we found that the CD5(hi) pool exhibited more efficient clonal recruitment and expansion, as well as enhanced reactivity to inflammatory cues, during recognition of foreign antigen. Yet foreign peptide–MHC recognition was similar for both subsets. Thus, CD8(+) T cells with higher self-reactivity dominate the immune response against foreign antigens, with implications for T cell repertoire diversity and autoimmunity.