Sculpting MHC class II-restricted self and non-self peptidome by the class I antigen-processing machinery and its consequences on TH cell responses

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It is generally assumed that the MHC class I antigen (Ag)-processing (CAP) machinery —which supplies peptides for presentation by class I molecules— plays no role in class II-restricted presentation of cytoplasmic Ags. In striking contrast to this assumption, we previously reported that proteasome inhibition or TAP- or ERAAP-deficiency led to dramatically altered T helper (TH) cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags. Herein, we tested whether altered Ag processing and presentation, altered CD4+ T cell repertoire, or both underlay the above finding. We found that TAP- and ERAAP-deficiency dramatically altered the quality of class II-associated self peptides suggesting that the CAP machinery impacts class II-restricted Ag processing and presentation. Consistent with altered self peptidomes, the CD4+ T cell receptor repertoire of mice deficient in the CAP machinery substantially differed from that of wildtype animals resulting in altered CD4+ T cell Ag recognition patterns. These data suggest that TAP and ERAAP sculpt the class II-restricted peptidome, impacting the CD4+ T cell repertoire, and ultimately altering TH cell responses. Together with our previous findings, these data suggest multiple CAP machinery components sequester or degrade MHC class II-restricted epitopes that would otherwise be capable of eliciting functional TH cell responses.