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TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8+ T cells

Nature Immunology volume 16, pages 10691076 (2015) | Download Citation

Abstract

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.

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Acknowledgements

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).

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Affiliations

  1. Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan.

    • Kensuke Takada
    •  & Yousuke Takahama
  2. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Francois Van Laethem
    •  & Alfred Singer
  3. Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Yan Xing
    •  & Stephen C Jameson
  4. Department of Immunology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.

    • Kazuyuki Akane
    •  & Haruhiko Suzuki
  5. Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.

    • Shigeo Murata
  6. Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

    • Keiji Tanaka

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Contributions

K. Takada and Y.T. conceived the study. K. Takada, S.C.J., A.S. and Y.T. designed the experiments. K. Takada, F.V.L., Y.X., K.A., H.S., S.M. and K. Tanaka performed the experiments. K. Takada, S.C.J., A.S. and Y.T. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yousuke Takahama.

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DOI

https://doi.org/10.1038/ni.3237

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