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Thymoproteasome and peptidic self

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Abstract

Positive selection of T cells in the thymus is induced by low-affinity TCR recognition of self-peptide-MHC complexes expressed by cortical thymic epithelial cells (cTECs). cTECs express a specialized type of proteasomes, the thymoproteasome, which generates a unique spectrum of MHC class I-associated peptides and plays a critical role in thymic positive selection of CD8+ T cells. However, it remains unclear how the thymoproteasome contributes to the thymic positive selection. More than 30 years ago, the “peptidic self” hypothesis proposed that TCRs recognize MHC-presented peptides only, without interacting with MHC molecules, which turned out to be incorrect. Interestingly, however, by implying that a set of MHC-associated peptides forms immunological self, this hypothesis also predicted that positive selection in the thymus is the primary immune response to “foreign epitope” peptides during T cell development. The thymoproteasome-dependent unique self-peptides may create those foreign epitope peptides displayed in the thymus for positive selection of T cells.

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Acknowledgements

The authors thank Dr. Alfred Singer (NCI, NIH, USA) for inspiring discussion and reading the manuscript and Dr. Tsunehiro Mizushima (University of Hyogo, Japan) for structural analysis of the proteasome components.

Funding

Y.T. is supported by the Intramural Research Program of the US National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research. In addition, Y.T., I.O., S.M., and K.T. are supported by MEXT-JSPS, Japan (grants 16H02630, 17K08884, 28H04022, and 26000014, respectively).

Author information

Authors and Affiliations

  1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Yousuke Takahama

  2. Institute of Advanced Medical Sciences, University of Tokushima, Tokushima, 770-8503, Japan

    Yousuke Takahama & Izumi Ohigashi

  3. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan

    Shigeo Murata

  4. Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan

    Keiji Tanaka

Authors
  1. Yousuke Takahama
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  2. Izumi Ohigashi
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  3. Shigeo Murata
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  4. Keiji Tanaka
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Corresponding author

Correspondence to Yousuke Takahama.

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This article is part of the Topical Collection on Biology and Evolution of Antigen Presentation

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Takahama, Y., Ohigashi, I., Murata, S. et al. Thymoproteasome and peptidic self. Immunogenetics 71, 217–221 (2019). https://doi.org/10.1007/s00251-018-1081-3

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