Abstract
Positive selection in the thymus provides low-affinity T-cell receptor (TCR) engagement to support the development of potentially useful self-major histocompatibility complex class I (MHC-I)-restricted T cells. Optimal positive selection of CD8+ T cells requires cortical thymic epithelial cells that express β5t-containing thymoproteasomes (tCPs). However, how tCPs govern positive selection is unclear. Here we show that the tCPs produce unique cleavage motifs in digested peptides and in MHC-I-associated peptides. Interestingly, MHC-I-associated peptides carrying these tCP-dependent motifs are enriched with low-affinity TCR ligands that efficiently induce the positive selection of functionally competent CD8+ T cells in antigen-specific TCR-transgenic models. These results suggest that tCPs contribute to the positive selection of CD8+ T cells by preferentially producing low-affinity TCR ligand peptides.
Highlights
Positive selection in the thymus provides low-affinity T-cell receptor (TCR) engagement to support the development of potentially useful self-major histocompatibility complex class I (MHC-I)-restricted T cells
Addition of N6 to the fetal thymus organ culture (FTOC) induced no significant effect onto the background cellularity of TCRhigh CD8 single-positive thymocytes in the presence of unrelated gp[33] (Fig. 7b); addition of S6 induced a clear increase in the generation of TCRhigh CD8 single-positive thymocytes, similar to other positive selection-inducing peptides (Fig. 7b); and addition of H7, as well as OVAp, to the FTOC induced a clear decrease in CD8 single-positive cells accompanied by depletion of CD4/CD8 double-positive cells, a hallmark of negative selection (Fig. 7a,b). These results indicate that tCP- and iCP-dependent motifs differently promote positive selection of CD8 þ T cells and suggest that tCP motif peptides are enriched for low-affinity peptides, whereas iCP motif peptides exhibit highly diverse TCR affinities from undetectable affinity to high affinity
These results suggest that abnormal positive selection induced in the absence of tCP, which is presumably induced by iCP-expressing cortical thymic epithelial cells (cTECs), is predominantly induced by the peptide ligands that exhibit different TCR affinity from the peptides normally expressed by tCP-expressing cTECs
Summary
Positive selection in the thymus provides low-affinity T-cell receptor (TCR) engagement to support the development of potentially useful self-major histocompatibility complex class I (MHC-I)-restricted T cells. Optimal positive selection of CD8 þ T cells requires cortical thymic epithelial cells that express b5t-containing thymoproteasomes (tCPs). MHC-Iassociated peptides carrying these tCP-dependent motifs are enriched with low-affinity TCR ligands that efficiently induce the positive selection of functionally competent CD8 þ T cells in antigen-specific TCR-transgenic models. These results suggest that tCPs contribute to the positive selection of CD8 þ T cells by preferentially producing low-affinity TCR ligand peptides. ICPs produce antigenic peptides for MHC-I more efficiently than cCPs and promote elimination of virus-infected cells by CD8 þ T cells. The other is the thymoproteasome, or tCP, which contains b5t in place of b5i/b5 along with b1i and b2i and is exclusively expressed in cortical thymic epithelial cells (cTECs)[13,14,15]
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