Crucial contribution of thymic Sirp alpha+ 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(-)CD8alpha(+) signal regulatory protein alpha (Sirpalpha)(-) and CD11c(+)B220(-)CD8alpha(-)Sirpalpha(+) conventional DCs (cDCs). However, the distinctive role of each DC subset remains undefined. We show herein that Sirpalpha(+) 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 Sirpalpha(+) but not Sirpalpha(-) cDC subset can selectively capture blood-circulating Ags. Moreover, in CCR2-deficient mice, the thymic Sirpalpha(+) 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(-)CD8alpha(-)Sirpalpha(+) cDCs can have a unique role in the development of central tolerance against circulating peripheral Ags, at least partially in a CCR2-dependent manner.