Abstract
The molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood. Here we show that B7-CD28 co-stimulation and B7 expression by specific antigen-presenting cell (APC) types are required for clonal deletion and for regulatory T (Treg) cell generation from endogenous tissue-restricted antigen (TRA)-specific thymocytes. While B7-CD28 interaction is required for both clonal deletion and Treg induction, these two processes differ in their CD28 signaling requirements and in their dependence on B7-expressing dendritic cells, B cells, and thymic epithelial cells. Meanwhile, defective thymic clonal deletion due to altered B7-CD28 signaling results in the accumulation of mature, peripheral TRA-specific T cells capable of mediating destructive autoimmunity. Our findings thus reveal a function of B7-CD28 co-stimulation in shaping the T cell repertoire and limiting autoimmunity through both thymic clonal deletion and Treg cell generation.
Highlights
The molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood
T cell receptor (TCR) that are strongly reactive to self-antigen-major histocompatibility complex (MHC) complexes are subjected to a process termed central tolerance, in which strongly self-reactive thymocytes are eliminated from the mature conventional T cell repertoire[1,2,3,4]
Requirement for some element(s) of the CD28 cytoplasmic tail in clonal deletion was demonstrated by the observation that clonal deletion of pMOG-specific Tconv was deficient in tail-less-CD28 (TL) Tg thymus[24] (Fig. 5e). These results indicate that while the PYAP but not YMNM motif was important for Treg cell generation, the clonal deletion was mediated by unidentified CD28 cytoplasmic region(s) other than YMNM and PYAP motifs
Summary
The molecular and cellular mechanisms mediating thymic central tolerance and prevention of autoimmunity are not fully understood. Defective thymic clonal deletion due to altered B7-CD28 signaling results in the accumulation of mature, peripheral TRA-specific T cells capable of mediating destructive autoimmunity. −CD8− double negative (DN) thymocytes, which are precursors of CD8αα intraepithelial lymphocytes (IEL)[11,12,13] These diverted populations are anergic or actively suppressive of anti-self responses, and do not mediate destructive autoimmunity. The second wave affects more mature SP cells in the thymic medulla, where for example, SP4 thymocyte expressing an αβ-TCR strongly reactive to self-antigenMHC II complexes are either deleted or diverted to Foxp3+ Treg cells[2,14,15].
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