B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance

Abstract

T-cell tolerance is the central program that prevents harmful immune responses against self-antigens, in which inhibitory PD-1 signal given by B7-H1 interaction plays an important role. Recent studies demonstrated that B7-H1 binds CD80 besides PD-1, and B7-H1/CD80 interaction also delivers inhibitory signals in T cells. However, a role of B7-H1/CD80 signals in regulation of T-cell tolerance has yet to be explored. We report here that attenuation of B7-H1/CD80 signals by treatment with anti-B7-H1 monoclonal antibody, which specifically blocks B7-H1/CD80 but not B7-H1/PD-1, enhanced T-cell expansion and prevented T-cell anergy induction. In addition, B7-H1/CD80 blockade restored Ag responsiveness in the previously anergized T cells. Experiments using B7-H1 or CD80-deficient T cells indicated that an inhibitory signal through CD80, but not B7-H1, on T cells is responsible in part for these effects. Consistently, CD80 expression was detected on anergic T cells and further up-regulated when they were reexposed to the antigen (Ag). Finally, blockade of B7-H1/CD80 interaction prevented oral tolerance induction and restored T-cell responsiveness to Ag previously tolerized by oral administration. Taken together, our findings demonstrate that the B7-H1/CD80 pathway is a crucial regulator in the induction and maintenance of T-cell tolerance. (Blood. 2010;116(8): 1291-1298) Introduction B7-H1 (CD274, PD-L1), a transmembrane glycoprotein belonging to immunoglobulin (Ig) superfamily molecule, plays an integral role in the regulation of immune tolerance and homeostasis. 1 Mice deficient of B7-H1 gene or wild-type mice treated with anti-B7-H1 blocking monoclonal antibody (mAb) exhibit exacerbated autoimmune phenotypes associated with an activation of self-reactive CD4 ϩ and CD8 ϩ T cells. [2][3][4][5] Tolerogenic functions of B7-H1 are dependent on its expression on hematopoietic or parenchymal cells, and mediated by its interaction with PD-1 receptor. 6-8 PD-1 is inducibly expressed on T cells after activation and delivers coinhibitory signals via immunoreceptor tyrosine-based switch motif in the cytoplasmic domain. 9,10 PD-1 signal interferes with phosphatidylinositol-3-kinase (PI3K) activity and subsequently inhibits interleukin-2 (IL-2) production, which eventually renders T cells anergic. 11 The mice deficient of PD-1 gene spontaneously develop autoimmune phenotypes, and single nucleotide polymorphisms of human PD-1 gene are associated with an increased risk of autoimmune diseases. [12][13][14][15][16] Recent studies by Butte et al discovered that B7-H1 interacts with CD80 (B7-1) in addition to PD-1. 17,18 In vitro studies using CD4ϩ T cells deficient of PD-1, CD28, and/or CTLA-4 indicated that B7-H1/CD80 interaction delivers bidirectional inhibitory signals to T cells. 17 These findings are consistent with previous observations implicating the presence of non-PD-1 receptor(s) of B7-H1. For instance, when the B7-H1/PD-1 interaction is blocked in models of T-cell tolerance, the effects of anti-B7-H1 antagonistic mAb in rest...

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

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