Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation.
Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.
Gallegos
Alena M
AM
Department of Immunology, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98795, USA.
Bevan
Michael J
MJ
D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology*; D001854:Bone Marrow Cells / Q000502:physiology; D001921:Brain / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology; D007108:Immune Tolerance; D007328:Insulin / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D010047:Ovalbumin / Q000276:immunology; D011401:Promoter Regions, Genetic; D051381:Rats
D000941:Antigens; D007328:Insulin; D010047:Ovalbumin