Proteasome alteration between epithelial and hematopoietic cells facilitates positive selection of CD8 T cells.

Authors

Mami Matsuda-Lennikov, Jamie-Jean De La Torre, Todd Snow, Jacqueline Battaile, Felix Kalle-Youngoue, Alison Jacques, Aya Ushio, Akihide Shimizu, Miho Shinzawa, Christian T Mayer, Parirokh Awasthi, Raj Chari, Izumi Ohigashi, Shigeo Murata, Yousuke Takahama

Published in

Nature communications. Volume 17. Issue 1. Apr 27, 2026. Epub Apr 27, 2026.

Abstract

The thymoproteasome, a proteolytic complex uniquely expressed in cortical thymic epithelial cells (cTECs), governs the positive selection of CD8 T cells. It has been hypothesized that the thymoproteasome promotes CD8 T cell development by forging a sequential switch in proteasome species between cTECs and medullary antigen-presenting cells (APCs), which generates a stepwise difference in MHC-I-associated peptides between cTECs and medullary APCs, thereby sparing positively selected thymocytes from subsequent negative selection. In this study, we engineer mice ectopically expressing thymoproteasomes in various APCs including medullary TECs (mTECs), eliminating the proposed proteasome switch. Surprisingly, we find that the proteasome switch between cTECs and mTECs is dispensable for thymoproteasome-dependent CD8 T cell development. Instead, we find that ectopic thymoproteasomes in hematopoietic cells impair CD8 T cell development by hindering cortical positive selection. Our findings reveal that the proteasome difference between cTECs and hematopoietic cells in the thymic cortex facilitates thymoproteasome-dependent positive selection.

PMID:
42045195
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

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