Implications of T cell receptor cross-reactivity on the CD4+ T cell repertoire (APP3P.111)

Abstract

Abstract Naïve CD4+ T cell populations with T cell receptors (TCR) specific for different major histocompatibility complex II (MHCII)-bound foreign peptides vary in size for unknown reasons. Negative selection on self peptides could play a role. We found that MHCII-binding nonamer peptides only had to have the same residues at five positions to be recognized by the same TCR. This degree of TCR cross-reactivity between self and foreign peptides reduced the sizes of foreign peptide-specific T cell populations via clonal deletion. Small foreign p:MHCII-specific populations that underwent a greater degree of cross-reactive negative selection were on average lower affinity and produced more variable effector cell responses to immunization. In contrast, large foreign p:MHCII-specific T cell populations with minimal evidence of negative selection were higher affinity and produced larger responses to immunization. Reciprocally, an incompletely deleted naïve T cell population specific for a tissue-restricted self peptide could be triggered by similar microbial peptides to cause autoimmunity. Thus, TCR cross-reactivity between similar self and foreign peptides influences the size of certain foreign peptide-specific T cell populations, and may allow tissue-restricted self peptide-specific populations to cause autoimmunity after infection.