Immunity 44 (5): 1114-1126 (2016-05-17)

Kieback E.; Hilgenberg E.; Stervbo U.; Lampropoulou V.; Shen P.; Bunse M.; Jaimes Y.; Boudinot P.; Radbruch A.; Klemm U.; Kuehl A.A.; Liblau R.; Hoevelmeyer N.; Anderton S.M.; Uckert W.; Fillatreau S.

Thymus-derived regulatory T cells are positively selected on natural self-antigen through cognate interactions of high functional avidity

Regulatory T (Treg) cells expressing Foxp3 transcripton factor are essential for immune homeostasis. They arise in the thymus as a separate lineage from conventional CD4(+)Foxp3(-) T (Tconv) cells. Here, we show that the thymic development of Treg cells depends on the expression of their endogenous cognate self-antigen. The formation of these cells was impaired in mice lacking this self-antigen, while Tconv cell development was not negatively affected. Thymus-derived Treg cells were selected by self-antigens in a specific manner, while autoreactive Tconv cells were produced through degenerate recognition of distinct antigens. These distinct modes of development were associated with the expression of T cell receptor of higher functional avidity for self-antigen by Treg cells than Tconv cells, a difference subsequently essential for the control of autoimmunity. Our study documents how self-antigens define the repertoire of thymus-derived Treg cells to subsequently endow this cell type with the capacity to undermine autoimmune attack.

Keywords: Autoantigens, CTLA-4 Antigen, Cultured Cells, Antigen-Mediated Clonal Selection, Experimental Autoimmune Encephalomyelitis, Forkhead Transcription Factors, Inbred C57BL Mice, Knockout Mice, Multiple Sclerosis, Myelin-Oligodendrocyte Glycoprotein, Peptide Fragments, T-Cell Antigen Receptors, T-Cell Antigen Receptor Specificity, T-Lymphocyte Subsets, Regulatory T-Lymphocytes, Thymus Gland, Animals, Mice

Type: Article

PubMed: 27192577
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