Crucial contribution of thymic Sirp alpha+ conventional dendritic cells to central tolerance against blood-borne antigens in a CCR2-dependent manner.
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.
Baba
Tomohisa
T
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
Nakamoto
Yasunari
Y
Mukaida
Naofumi
N
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000097:blood* / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000145:classification* / Q000276:immunology* / Q000378:metabolism; D004705:Endocytosis / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood / Q000276:immunology; D054390:Receptors, CCR2 / Q000097:blood / Q000172:deficiency / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000097:blood; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; C515335:Ccr2 protein, mouse; C111390:OVA 323-339; D010446:Peptide Fragments; C501922:Sirpa protein, mouse; D054390:Receptors, CCR2; D011971:Receptors, Immunologic; D010047:Ovalbumin