Abstract
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.
Highlights
Central tolerance is induced in the thymus, where developing thymocytes that recognize self-peptide–MHC complexes with too high affinity are deleted
The final reason we chose rat insulin promoter (RIP)-mOVA as a model tissue-specific antigen (TSA) is because thymic deletion of OVA-specific T cells in these mice is known to be dependent on the thymic expression of OVA and is not the result of OVA reaching the thymus from the periphery, either via blood or from a migrating antigen-presenting cells (APCs) [20]
The fact that only rare medullary thymic epithelial cell (Mtec) express a given TSA (ف1-5% of Mtecs in cases that have been analyzed; references 3, 5, 11, 13, and 14), plus the fact that epithelial cells might be poor at presenting antigen for T cell deletion, led us to propose that indirect or cross-presentation of Mtec-derived TSA by DCs would be key in inducing efficient central tolerance to TSA
Summary
Central tolerance is induced in the thymus, where developing thymocytes that recognize self-peptide–MHC complexes with too high affinity are deleted. Studies analyzing [Parent→F1] BM chimeras or thymus-grafted animals conclusively demonstrated that BMderived cells are strong inducers of thymic tolerance, whereas tolerance induction by tecs is incomplete [1, 2]. Most of these experiments analyzed central tolerance to antigens that are widely expressed in many or all tissues. Transgenic antigen, driven off tissue-specific promoters, results in thymic expression of antigen and elimination of T cells reactive against these antigens [10, 11] Such T cells are rescued from deletion when they develop in AIRE-deficient thymuses [12]. These data demonstrate that there is strong central tolerance to TSA and that this process is required for the maintenance of self-tolerance
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