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<p>Dendritic cells are essential for establishing thymic central tolerance; however, mechanisms supporting their homeostasis and activation remain unresolved. Through single-cell transcriptomics and functional assays, we identify seven thymic conventional dendritic cell (cDC) subsets and discriminate their abilities to present self-antigens and induce regulatory T cells. Mice blocked at different stages of T cell development revealed that CD4<sup>+</sup> single-positive (CD4SP) and CD8SP thymocytes differentially support homeostasis and activation of type 1 cDCs (cDC1s) versus cDC2s/plasmacytoid DCs (pDCs), respectively. CD8SP thymocytes indirectly support pDC survival and cDC2 thymic migration, and they induce interferon signaling in cDCs, partly by promoting type 3 interferon expression by medullary thymic epithelial cells. By contrast, CD4SP thymocytes undergo cognate interactions with cDCs, inducing CD40 signaling required for activation of cDC1s. Activated cDC1s make nonredundant contributions to central tolerance. Together, this study comprehensively identifies distinct thymic DC subsets and elucidates requirements for cross-talk with thymocyte subsets that support their homeostasis, activation and function.</p>

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The differentiation and function of heterogeneous thymic dendritic cell subsets require signals provided by distinct thymocyte cell types

  • 期刊论文

  • 发表日期：

    2026年1月8日

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  • Jayashree Srinivasan,
  • Colin R. Moore,
  • Aparna Calindi,
  • Bryan R. Helm,
  • Yilin Yang,
  • John F. Moore,
  • Hilary J. Selden,
  • Cody N. Heiser,
  • Qi Liu,
  • Ken S. Lau,
  • Lauren I. R. Ehrlich

摘要

Dendritic cells are essential for establishing thymic central tolerance; however, mechanisms supporting their homeostasis and activation remain unresolved. Through single-cell transcriptomics and functional assays, we identify seven thymic conventional dendritic cell (cDC) subsets and discriminate their abilities to present self-antigens and induce regulatory T cells. Mice blocked at different stages of T cell development revealed that CD4+ single-positive (CD4SP) and CD8SP thymocytes differentially support homeostasis and activation of type 1 cDCs (cDC1s) versus cDC2s/plasmacytoid DCs (pDCs), respectively. CD8SP thymocytes indirectly support pDC survival and cDC2 thymic migration, and they induce interferon signaling in cDCs, partly by promoting type 3 interferon expression by medullary thymic epithelial cells. By contrast, CD4SP thymocytes undergo cognate interactions with cDCs, inducing CD40 signaling required for activation of cDC1s. Activated cDC1s make nonredundant contributions to central tolerance. Together, this study comprehensively identifies distinct thymic DC subsets and elucidates requirements for cross-talk with thymocyte subsets that support their homeostasis, activation and function.