In the thymus, low-affinity T cell antigen receptor (TCR) engagement facilitates positive selection of a useful T cell repertoire. Here we report that TCR responsiveness of mature CD8 + T cells is fine tuned by their affinity for positively selecting peptides in the thymus and that optimal TCR responsiveness requires positive selection on major histocompatibility complex class I-associated peptides produced by the thymoproteasome, which is specifically expressed in the thymic cortical epithelium. Thymoproteasome-independent positive selection of monoclonal CD8 + T cells results in aberrant TCR responsiveness, homeostatic maintenance and immune responses to infection. These results demonstrate a novel aspect of positive selection, in which TCR affinity for positively selecting peptides produced by thymic epithelium determines the subsequent antigen responsiveness of mature CD8 + T cells in the periphery.
Bibliographical noteFunding Information:
We thank H. Kosako, I. Ohigashi, M. Kozai and B. Kim for helpful discussion and reading the manuscript. This work was supported by grants from MEXT-JSPS (24111004 and 23249025 to Y.T. and 24790475 and 26460576 to K. Takada), Naito Foundation (to Y.T. and K. Takada), Takeda Science Foundation (to K. Takada), and Uehara Memorial Foundation (to K. Takada).