Crucial Contribution of Thymic Sirpα+ Conventional Dendritic Cells to Central Tolerance against Blood-Borne Antigens in a CCR2-Dependent Manner

Abstract

Thymic dendritic cells (DCs) as well as thymic epithelial cells are presumed to be major sentinels in central tolerance by inducing the apoptosis of autoreactive T progenitor cells. The thymic DC population is composed of heterogeneous subsets including CD11c+B220+ plasmacytoid DCs, CD11c+B220−CD8α+ signal regulatory protein α (Sirpα)− and CD11c+B220−CD8α−Sirpα+ conventional DCs (cDCs). However, the distinctive role of each DC subset remains undefined. We show herein that Sirpα+ cDCs, a minor subpopulation, was disseminated in the thymic cortical area with some of them uniquely localized inside perivascular regions and nearby small vessels in the thymus. The Sirpα+ but not Sirpα− cDC subset can selectively capture blood-circulating Ags. Moreover, in CCR2-deficient mice, the thymic Sirpα+ cDC subset, but not other thymic cell components, was moderately decreased especially in the perivascular regions. Concomitantly, these mice exhibited a modest impairment in intrathymic negative selection against blood-borne Ags, with the reduced capacity to uptake blood-borne Ags. Given their intrathymic cortical localization, CD11c+B220−CD8α−Sirpα+ cDCs can have a unique role in the development of central tolerance against circulating peripheral Ags, at least partially in a CCR2-dependent manner.