Immunomodulatory Functions of BTLA and HVEM Govern Induction of Extrathymic Regulatory T Cells and Tolerance by Dendritic Cells

Dendritic cells (DCs) initiate immunity and also antigen-specific tolerance mediated by extrathymic regulatory T (Treg) cells, yet it remains unclear how DCs regulate induction of such tolerance. Here, we report that efficient induction of Treg cells was instructed by BTLA⁺DEC205⁺CD8⁺CD11c⁺ DCs and the immunomodulatory functions of BTLA. In contrast, T cell activation in steady state by total CD11c⁺ DCs that include a majority of DCs that do not express BTLA did not induce Treg cells and had no lasting impact on subsequent immune responses. Engagement of HVEM, a receptor of BTLA, promoted Foxp3 expression in T cells through upregulation of CD5. In contrast, T cells activated in the absence of BTLA and HVEM-mediated functions remained CD5^lo and therefore failed to resist the inhibition of Foxp3 expression in response to effector cell-differentiating cytokines. Thus, DCs require BTLA and CD5-dependent mechanisms to actively adjust tolerizing T cell responses under steady-state conditions.