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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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  • 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

摘要

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.