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

Nat Commun. 2015 Jun 23;6:7484. doi: 10.1038/ncomms8484.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Blotting, Western
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation
  • Cell Line
  • Epithelial Cells
  • Flow Cytometry
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class I / metabolism*
  • In Vitro Techniques
  • Mice
  • Peptide Fragments / metabolism*
  • Proteasome Endopeptidase Complex / metabolism*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Thymus Gland / immunology
  • Thymus Gland / metabolism

Substances

  • Histocompatibility Antigens Class I
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Proteasome Endopeptidase Complex
  • proteasome subunit beta5t, mouse