Establishment of CD8+ T cell thymic central tolerance to tissue-restricted antigen requires PD-1

Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted antigen (TRA) did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. PD-1 was induced in the thymus and was required to establish cell-intrinsic tolerance to TRA in CD8+ thymocytes independently of clonal deletion. PD-1 signaling in developing thymocytes was sufficient for tolerance induction, however in some cases the absence of PD-L1-mediated signaling in the periphery resulted in broken tolerance at late time points. Finally, we showed that chronic exposure to high affinity antigen supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti-PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/502412v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1e3d786org.highwire.dtl.DTLVardef@15aaaaaorg.highwire.dtl.DTLVardef@17ab803org.highwire.dtl.DTLVardef@1c6e23b_HPS_FORMAT_FIGEXP M_FIG C_FIG