Soluble CTLA-4 mainly produced by Treg cells inhibits type 1 inflammation without hindering type 2 immunity to allow for inflammation resolution

Abstract

CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms. Here, we found that effector-type regulatory T cells (Tregs) are main sCTLA-4 producers in basal and inflammatory states. We generated sCTLA-4-intact mCTLA-4-deficient mice, which spontaneously developed systemic inflammation distinct from that in double-deficient mice, with predominant activation/differentiation of Th2, M2-like macrophages, and eosinophils. In contrast, sCTLA-4-deficient mCTLA-4-intact mice exhibited spontaneous activation of Th1, Th17, Tfh, and Tc1 cells, production of autoantibody and IgE, M1-like macrophage polarization, and impaired wound healing. Consistently, recombinant sCTLA-4 inhibited in vitro differentiation of naive T cells towards Th1, while allowing Th2 differentiation, through CD80/CD86 blockade on antigen-presenting cells. Moreover, sCTLA-4-intact mCTLA-4-deficient Tregs effectively suppressed Th1-mediated experimental colitis whereas double-deficient Tregs did not. Thus, sCTLA-4 not only suppresses T-cell activation in the steady state but also selectively inhibits type 1 in favor of type 2 immunity during chronic inflammation. sCTLA-4 is, therefore, a viable therapeutic candidate for inflammatory diseases and cancer.

Rigid, bivalent CTLA-4 binding to CD80 is required to disrupt thecisCD80 / PD-L1 interaction

“…Moreover, abatacept may prevent cell-expressed CTLA-4 from interacting with CD80 and thereby preclude release of PD-L1 via transendocytosis. Another relevant consideration is that a secreted soluble CTLA-4 isoform might also affect PD-L1 activity 35,36 . However, this splice variant lacks the cysteine responsible for forming covalent dimers and displays changes in the stalk region which appear to preclude both non-covalent and covalent interactions.…”