Distinct thymic pDC populations promote tumor immune tolerance through complementary mechanisms

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Thymic central tolerance is crucial for preventing autoimmunity, but its contribution to tumor immune evasion remains poorly understood. Here, we demonstrate that plasmacytoid dendritic cells (pDCs) in the thymus have two distinct subsets, accumulating in the thymus of tumor-bearing mice, contributing to immune tolerance through clonal deletion of tumor-specific T cells and reducing newly generated T cells. Mechanistically, common dendritic cell progenitor-derived pDCs (CDP-pDCs) capture tumor antigens and migrate to the thymus in a CCR9-dependent manner, where they present these antigens to induce clonal deletion of tumor-specific T cells. Concurrently, tumor progression inhibits T cell generation by promoting the accumulation of common lymphoid progenitor-derived pDCs (CLP-pDCs) within the thymus, which further produce type I interferon to alter thymic function. CCR9 deficiency prevents thymic accumulation of both pDCs, enhancing antitumor immunity and reducing tumor growth. Our findings reveal a previously unrecognized mechanism by which tumors hijack the physiological system to establish central tolerance against peripheral antigens, thereby promoting tolerance against themselves.

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