Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation

TLDR

Intrathymic expression of tissue‑specific antigens by medullary thymic epithelial cells induces deletion of autoreactive T cells, but it was unclear whether this tolerance is mediated directly by Mtecs or indirectly via bone‑marrow‑derived APCs. The study demonstrates that bone‑marrow‑derived APCs cross‑present TSAs from Mtecs to delete autoreactive CD4 and CD8 T cells, while Mtecs directly delete CD8 T cells but not CD4, revealing a cooperative mechanism that expands clonal deletion during thymic maturation.

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.