Thymoproteasomes produce unique peptide motifs for positive selection of CD8+ T cells

Katsuhiro Sasaki, Kensuke Takada, Yuki Ohte, Hiroyuki Kondo, Hiroyuki Sorimachi, Keiji Tanaka, Yousuke Takahama () and Shigeo Murata ()
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Katsuhiro Sasaki: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Kensuke Takada: Institute for Genome Research, University of Tokushima
Yuki Ohte: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Hiroyuki Kondo: Institute for Genome Research, University of Tokushima
Hiroyuki Sorimachi: Calpain Project, Tokyo Metropolitan Institute of Medical Science
Keiji Tanaka: Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science
Yousuke Takahama: Institute for Genome Research, University of Tokushima
Shigeo Murata: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8484

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