Soluble CD137 produced by Foxp3+ regulatory CD4 T cells is immunosuppressive and restrains ongoing autoimmune diabetes

CD137 (4-1BB) is expressed in a subset of Foxp3+ regulatory CD4 T cells (Tregs) but its role in Treg function is not completely clear. Due to alternative splicing that excises the transmembrane domain coding exon, CD137 is expressed as cell surface and soluble forms. We studied the function of CD137 in Tregs using the NOD mouse model of autoimmune type 1 diabetes (T1D). Treg-specific deletion of CD137 resulted in significant reduction of circulating soluble CD137 and considerably accelerated T1D development because of heightened clonal expansion and differentiation of effector T cells in pancreatic islets. CD137 deficiency in Tregs reduced their accumulation in islets and negatively impacted their differentiation trajectory toward a highly suppressive phenotype. Restoring Treg-derived soluble CD137 reduced islet T cell activation and delayed T1D onset without affecting the accumulation of phenotypically suppressive Tregs. Thus, as a major in vivo source, Treg-derived soluble CD137 participates in autoimmune control.