title: MHC-mismatched mixed chimerism mediates thymic deletion of cross-reactive autoreactive T cells and prevents insulitis in nonobese diabetic mice.
abstract: Type 1 diabetic NOD mice have defects in both thymic negative selection and peripheral regulation of autoreactive T cells, and induction of mixed chimerism can effectively reverse these defects. Our recent studies suggest that MHC-mismatched mixed chimerism mediates negative selection of autoreactive thymocytes in wild-type NOD and TCR-transgenic NOD.Rag1(+/+).BDC2.5 mice. However, it remains unknown how mismatched I-A(b) MHC class II can mediate deletion of autoreactive T cells positively selected by I-A(g7). In the present study, we directly tested the hypothesis that mismatched MHC class II in mixed chimeras mediates deletion of cross-reactive autoreactive thymocytes. We first identify that transgenic BDC2.5 T cells from NOD.Rag1(+/+).BDC2.5 but not NOD.Rag1(-/-).BDC2.5 mice possess cross-reactive TCRs with endogenous TCRα-chains; MHC-mismatched H-2(b) but not matched H-2(g7) mixed chimerism mediates thymic deletion of the cross-reactive transgenic T cells in NOD.Rag1(+/+).BDC2.5 mice. Second, by transplanting T cell-depleted (TCD) bone marrow (BM) cells from NOD.Rag1(+/+).BDC2.5 or NOD.Rag1(-/-).BDC2.5 mice into lethally irradiated MHC-mismatched H-2(b) C57BL/6 or MHC-matched congenic B6.H-2(g7) recipients, we demonstrate that NOD.Rag1(+/+).BDC2.5 BM-derived cross-reactive transgenic T cells, but not NOD.Rag1(-/-).BDC2.5 BM-derived non-cross-reactive transgenic T cells, can be positively selected in MHC-mismatched H-2(b) thymus. Third, by cotransplanting NOD.Rag1(+/+).BDC2.5 TCD BM cells with BM cells from MHC-mismatched T cell-deficient C57BL/6 mice into lethally irradiated MHC-matched B6.H-2(g7) recipients, we demonstrate that thymic deletion of the cross-reactive transgenic T cells is dependent on MHC-mismatched donor BM-derived APCs but not on donor BM-derived T cells. Taken together, our studies indicate that MHC-mismatched mixed chimerism can mediate thymic deletion of cross-reactive autoreactive T cells that express more than one TCR.
authors.affiliation: Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010; Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010; and.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Racine
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010; and.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010; and.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Eugene and Ruth Roberts Summer Student Academy, Beckman Research Institute, City of Hope, Duarte, CA 91010.
authors.forename: William
authors.initials: W
authors.lastname: Morales
authors.affiliation: Eugene and Ruth Roberts Summer Student Academy, Beckman Research Institute, City of Hope, Duarte, CA 91010.
authors.forename: Christine
authors.initials: C
authors.lastname: Shen
authors.affiliation: Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010; Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010; and dzeng@coh.org.
authors.forename: Defu
authors.identifier: http://orcid.org/0000-0001-9585-1411
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D046528:Chimerism; D003429:Cross Reactions / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D060168:Thymocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; D018398:Homeodomain Proteins; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein