HVEM expressed in CD4 T cells promotes self-tolerance to an epidermal antigen through Treg expansion and modulation of B cell responses.

Autoreactive T and B cells recognizing tissue-associated self-antigens are tolerized in the periphery, where dendritic cells (DCs) initiate the inactivation of autoreactive T cells. Here, we generated a mouse model in which a neo-self-antigen is expressed in the epidermis and examined interactions between DCs and antigen-specific CD4 T cells, as well as between CD4 T cells and B cells under tolerant conditions. We found that one of the tumor necrosis factor receptor superfamily (TNFRSF) molecules, herpesvirus entry mediator (HVEM), in CD4 T cells performs two key functions: it promotes regulatory T cell (Treg) expansion in response to epidermal antigen and suppresses B cell activation by sending inhibitory signals. HVEM-deficient Tregs failed to respond to self-antigen-loaded migratory DCs from the skin, whereas HVEM-deficient CD4 T cells enhanced B cell activation, leading to increased IgG1+ B cells. These findings demonstrate that HVEM in CD4 T cells contributes to peripheral tolerance to tissue-associated self-antigens by promoting Treg expansion and restraining B cell responses.