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<p>Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both <i>Cd4</i> and <i>Cd8</i> gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8<sup>+</sup> T cell subsets. Strikingly, such mice revealed that functionally different CD8<sup>+</sup> T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8<sup>+</sup> T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8<sup>+</sup> T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8<sup>+</sup> T cells, integrating peptide specificity and CD8<sup>+</sup> T cell function during positive selection and thymocyte migration.</p>

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Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月19日

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  • Miho Shinzawa,
  • Nicole Ramos,
  • Khanh Bui,
  • William Hajjar,
  • Assiatu Crossman,
  • Xiongfong Chen,
  • Margaret Cam,
  • Yousuke Takahama,
  • Alfred Singer

摘要

Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both Cd4 and Cd8 gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8+ T cell subsets. Strikingly, such mice revealed that functionally different CD8+ T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8+ T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8+ T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8+ T cells, integrating peptide specificity and CD8+ T cell function during positive selection and thymocyte migration.