Orabona Ciriana, Belladonna Maria Laura, Vacca Carmine, Bianchi Roberta, Fallarino Francesca, Volpi Claudia, Gizzi Stefania, Fioretti Maria Cristina, Grohmann Ursula, Puccetti Paolo
Department of Experimental Medicine, University of Perugia, Italy.
J Immunol. 2005 Jun 1;174(11):6582-6. doi: 10.4049/jimmunol.174.11.6582.
CTLA-4-Ig and CD28-Ig are both agonist ligands of B7 coreceptor molecules on mouse dendritic cells (DCs), yet they bias the downstream response in opposite directions, and CTLA-4-Ig promotes tolerance, whereas CD28-Ig favors the onset of immunity. Although B7 engagement by either ligand leads to a mixed cytokine response, a dominant IL-6 production in response to CD28-Ig prevents the IFN-gamma-driven induction of immunosuppressive tryptophan catabolism mediated by IDO. In the present study, we show that silencing the expression of suppressor of cytokine signaling 3 (SOCS3) in DCs by RNA interference renders CD28-Ig capable of activating IDO, likely as a result of unrestrained IFN-gamma signaling and IFN-gamma-like actions of IL-6. Thus, in the absence of SOCS3, CD28-Ig becomes immunosuppressive and mimics the action of CTLA-4-Ig on tryptophan catabolism.
CTLA-4-Ig和CD28-Ig都是小鼠树突状细胞（DCs）上B7共受体分子的激动剂配体，但它们使下游反应偏向相反方向，CTLA-4-Ig促进耐受性，而CD28-Ig有利于免疫反应的启动。尽管任一配体与B7结合都会导致混合的细胞因子反应，但对CD28-Ig的反应中占主导地位的IL-6产生可防止由吲哚胺2,3-双加氧酶（IDO）介导的IFN-γ驱动的免疫抑制性色氨酸分解代谢的诱导。在本研究中，我们表明通过RNA干扰沉默DCs中细胞因子信号转导抑制因子3（SOCS3）的表达使CD28-Ig能够激活IDO，这可能是由于不受限制的IFN-γ信号传导以及IL-6的IFN-γ样作用所致。因此，在缺乏SOCS3的情况下，CD28-Ig具有免疫抑制作用，并模拟CTLA-4-Ig对色氨酸分解代谢的作用。
