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bioRxiv · 10.1101/2023.05.26.542386

Soluble CTLA-4 mainly produced by Treg cells inhibits and resolves type 1 inflammation but allows type 2 immunity

Osaki, M.·Sakaguchi, S.
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Abstract

CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms. Here, we show that effector-type regulatory T cells (Tregs) are main sCTLA-4 producers in basal and inflammatory states with distinct kinetics upon TCR stimulation. Mice specifically deficient in sCTLA-4 production exhibited spontaneous activation of Th1, Th17, Tfh, and Tc1 cells, autoantibody and IgE production, M1-like macrophage polarization, and impaired wound healing. In contrast, sCTLA-4-intact mCTLA-4-deficient mice, when compared with double-deficient mice, developed milder systemic inflammation and showed predominant activation/differentiation of Th2, M2-like macrophages, and eosinophils. Consistently, recombinant sCTLA-4 inhibited in vitro differentiation of naive T cells towards Th1 through CD80/CD86 blockade on antigen-presenting cells, but did not affect Th2 differentiation. Moreover, sCTLA-4-intact mCTLA-4-deficient Tregs effectively suppressed Th1-mediated experimental colitis whereas double-deficient Tregs did not. Thus, sCTLA-4 production by Tregs during chronic inflammation is instrumental in controlling type 1 immunity while allowing type 2 immunity to dominate and facilitate inflammation resolution.

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Osaki, M., Sakaguchi, S.. 2023-05-26. Soluble CTLA-4 mainly produced by Treg cells inhibits and resolves type 1 inflammation but allows type 2 immunity. https://doi.org/10.1101/2023.05.26.542386

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