Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR/GITR‐L interaction, IL‐10 and TGF‐β

Regulatory T cells exert their function through the modulation of both T and B cell responses. Our previous studies demonstrated that IL‐10‐producing Treg (Tr1) can induce B cells to secrete IgG4 in a cell‐contact‐dependent manner. The benefit of such non‐inflammatory B‐cell responses is apparent in the hyporesponsive state of patients with helminth infections such as Onchocerciasis. Here, we investigated the mechanisms involved to induce IgG4, within B:Tr‐cell co‐cultures, using IL‐10‐producing tetanus‐toxoid‐specific regulatory T cell lines and clones (Tr‐TCC) from human PBMC. During the generation process, we found that increasing Foxp3 levels in regulatory T cell lines correlated with their ability to induce IgG4 in B cells. Using Tr‐TCC, we found that blocking glucocorticoid‐induced tumour necrosis factor receptor‐related protein (GITR) molecules selectively prevented IgG4 production as did neutralizing Ab to glucocorticoid‐induced tumour necrosis factor receptor‐related protein ligand (GITR‐L), IL‐10 and TGF‐β. Furthermore, the prevention of IgG4 induction by anti‐GITR Ab was reversed by excess rIL‐10 but not rTGF‐β. In contrast, anti‐ICOS and anti‐CTLA‐4 Abs had no effect. When compared with Tr‐TCC, freshly isolated CD4+CD25+ T cells, but not effector T cell populations, induced low levels of IgG4, which were also blocked by anti‐GITR and anti‐GITR‐L Ab. Thus, the mechanism of IgG4 induction by regulatory cells involves GITR–GITR‐L interactions, IL‐10 and TGF‐β.