Fig. 2.

Thymoproteasome and thymic selection. (A) Thymic selection in normal thymus. cTEC-specific thymoproteasome produces a unique set of MHC-I-associated peptides (red symbols) that induce positive selection in the thymic cortex. Positively selected thymocytes (red cells) are screened for negative selection in the cortex and medulla, and a fraction of thymocytes are negatively selected to establish self-tolerance. (B) According to the peptide switch hypothesis, positive selection-inducing MHC-associated peptides must be different from negative selection-inducing MHC-associated peptides. In the conditions that lack the machinery to produce a unique set of MHC-I-associated peptides, a set of MHC-I-associated peptides identical to negative selection-inducing peptides (yellow symbols) are displayed by cTECs and positively select a repertoire of thymocytes in the thymic cortex; however, these thymocytes are subsequently negatively selected in the thymus by the interaction with identical set of MHC-I-associated peptides. Thus, the lack of the peptide switch may not reduce the number of positively selected thymocytes in the cortex (yellow cells) but may enhance the number of negatively selected thymocytes. (C) However, it was shown that in the thymus of β5t-knockout (KO) mice, the number of positively selected thymocytes in the cortex are reduced (green cells), whereas the number of negatively selected thymocytes are not elevated. Thus, the thymoproteasome optimizes CD8⁺ T cell development by supporting positive selection in the cortex independent of negative selection. The impaired generation of CD8⁺ T cells in β5t-deficient thymus is primarily due to impaired positive selection in the cortex. (D) How does the thymoproteasome work? The thymoproteasome expressed in WT cTECs produces MHC-I-associated peptides (red) that may possess structural advantage to interact with MHC-I-restricted TCR structures (for example, TCRα#1-containing TCRs as described in Section 3.3) that are preferentially used in efficiently induce positive selection of CD8⁺ T cells. However, MHC-I-associated peptides (green) displayed by β5t-knockout (KO) cTECs, which are produced independent of the thymoproteasomes, may lack such structural advantage and fail to induce to positive selection of CD8⁺ T cells.