T cell cross-reactivity to self peptide:MHCII shapes the foreign peptide: MHCII-specific CD4+ T cell repertoire (APP2P.112)

Abstract

Abstract The sizes of naïve CD4+ T cell populations specific for different foreign peptide:major histocompatibility complex II (p:MHCII) ligands vary by several orders of magnitude. This variability is biologically significant because large naïve populations generate more effector cells during an immune response than small ones. We hypothesized that the size of a given foreign p:MHCII-specific population is influenced by negative selection due to cross-reactivity between the foreign peptide and self peptides. We found that the frequency of naïve T cells specific for a given foreign p:MHCII ligand was inversely related to the number of self peptides predicted to bind MHCII and sharing 4 TCR contact amino acids with the foreign peptide. In addition, foreign p:MHCII-specific populations that were very small in normal mice were preferentially increased in mice with defective negative selection. Furthermore, gene-targeted mice lacking individual self peptides predicted to be involved in negative selection showed increased responsiveness to cross-reactive foreign peptides. These results suggest that immunodominant foreign peptides have this property because the corresponding naïve CD4+ T cell population has been subjected to minimal negative selection on cross-reactive self peptides.