title: Novel process of intrathymic tumor-immune tolerance through CCR2-mediated recruitment of Sirpα+ dendritic cells: a murine model.
abstract: Immune surveillance system can detect more efficiently secretory tumor-specific antigens, which are superior as a target for cancer immunotherapy. On the contrary, immune tolerance can be induced in the thymus when a tumor antigen is massively secreted into circulation. Thus, the secretion of tumor-specific antigen may have contradictory roles in tumor immunity in a context-dependent manner. However, it remains elusive on the precise cellular mechanism of intrathymic immune tolerance against tumor antigens. We previously demonstrated that a minor thymic conventional dendritic cell (cDC) subset, CD8α(-)Sirpα(+) cDCs, but not the major subset, CD8α(+)Sirpα(-) cDCs can selectively capture blood-borne antigens and crucially contribute to the self-tolerance. In the present study, we further demonstrated that Sirpα(+) cDCs can capture a blood-borne antigen leaking inside the interlobular vascular-rich regions (IVRs). Blood-borne antigen selectively captured by Sirpα(+) cDCs can induce antigen-specific Treg generation or negative selection, depending on the immunogenicity of the presented antigen. Furthermore, CCR2 expression by thymic Sirpα(+) cDCs and abundant expression of its ligands, particularly, CCL2 by tumor-bearing mice prompted us to examine the function of thymic Sirpα(+) cDCs in tumor-bearing mice. Interestingly, tumor-bearing mice deposited CCL2 inside IVRs in the thymus. Moreover, tumor formation induced the accumulation of Sirpα(+) cDCs in IVRs under the control of CCR2-CCL2 axis and enhanced their capacity to take up antigens, resulting in the shift from Treg differentiation to negative selection. Finally, intrathymic negative selection similarly ensued in CCR2-competent mice once the tumor-specific antigen was secreted into bloodstream. Thus, we demonstrated that thymic Sirpα(+) cDCs crucially contribute to this novel process of intrathymic tumor immune tolerance.
authors: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan. sergenti@staff.kanazawa-u.ac.jp
authors: Tomohisa
authors: T
authors: Baba
authors: Mohamed El Sherif
authors: Mel S
authors: Badr
authors: Utano
authors: U
authors: Tomaru
authors: Akihiro
authors: A
authors: Ishizu
authors: Naofumi
authors: N
authors: Mukaida
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis*; D018845:CD11 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D003713:Dendritic Cells / Q000378:metabolism*; D017353:Gene Deletion; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D011485:Protein Binding; D054390:Receptors, CCR2 / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000096:biosynthesis*; D060168:Thymocytes / Q000166:cytology
chemical_list: D000943:Antigens, Differentiation; C515334:CCR2 protein, human; D018845:CD11 Antigens; C515335:Ccr2 protein, mouse; D007376:Interleukin-2; D008024:Ligands; C501922:Sirpa protein, mouse; D054390:Receptors, CCR2; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D049452:Green Fluorescent Proteins