T cell receptor (TCR) cross-reactivity between major histocompatibility complex II (MHCII)-binding self and foreign peptides could influence the naive CD4+ Tcell repertoire and autoimmunity. We found that nonamer peptides that bind to the same MHCII molecule only need to share five amino acids to cross-react on the same TCR. This property was biologically relevant because systemic expression of a self peptide reduced the size of a naive cell population specific for a related foreign peptide by deletion of cells with cross-reactive TCRs. Reciprocally, an incompletely deleted naive Tcell population specific for a tissue-restricted self peptide could be triggered by related microbial peptides to cause autoimmunity. Thus, TCR cross-reactivity between similar self and foreign peptides can reduce the size of certain foreign peptide-specific Tcell populations and might allow Tcell populations specific for tissue-restricted self peptides to cause autoimmunity after infection.
Bibliographical noteFunding Information:
We thank J. Walter and A. Quade for technical assistance, S. McSorley for the Aasf:I-A b , RplF:I-A b , and PmpG1:I-A b tetramers, and all members of the Jenkins Laboratory for helpful discussions. Grants from the NIH (T32 GM008244 and F30 DK093242 to R.W.N., UL1 TR000114 to D.B., R01 AI107020 to J.J.M., R01 AI080275 to K.N., R01 AI105816 and R01 AI040996 to B.S.K., R01 AI093553 to M.W., P01 AI035296 to B.T.F., and R37 AI027998, R01 AI039614, P01 AI035296, and R01 AI103760 to M.K.J.) and the William F. Milton Fund (to J.J.M.) supported this work.