Deciphering the Nature of The Peptide Repertoire Supporting Positive Selection of CD8 T cells

点击翻译按钮获取中文摘要

The thymus is the sole organ capable of supporting the development of two major subsets of lymphocytes known as conventional and innate T cells. However, no direct mechanism(s) has been proposed to explain the dogma behind their divergent development. One untested possibility stipulates differences in T-cell receptor (TCR) signal strength as a major determinant of adopting a conventional versus innate fate. Examples supporting this hypothesis rely on the observation that innate, but not conventional CD8 T cells, express several activation markers whose expression is proportional to the signal strength perceived during their intrathymic development. In fact, TCR signal strength depends on both cell surface density and affinity to major histocompatibility I(MHCI)-peptide complexes presented on the surface of cortical thymic epithelial cells (cTECs). The generation of these complexes relies on the cTECs proteasomal machinery, which is mainly composed of thymoproteasomes and a minor fraction of immunoproteasomes (two distinct forms of proteasomes). As the thymoproteasome generates low affinity peptides, unstable MHCI-peptide complexes are yielded delivering therefore weaker TCR stimulation. In contrast, immunoproteasome-dependent MHCI-peptide complexes are more stable and thus, endowed with the capacity of eliciting stronger TCR signals. Interestingly, thymoproteasome-deficient mice (although expressing immunoproteasomes in cTECs) lack conventional CD8 T cells but harbor a noticeable increase in the proportion of peripheral memory/innate-like CD8 T cells. Based on these observations, we hypothesize that innate CD8 thymocytes are selected by immunoproteasome-dependent peptides in contract to conventional CD8 thymocytes, which rely preferentially on peptides generated via the thymoproteasome.