Regulatory T cells mediate specific suppression by depleting peptide–MHC class II from dendritic cells

Regulatory T cells (T reg cells) can activate multiple suppressive mechanisms in vitro after activation via the T cell antigen receptor, resulting in antigen-independent suppression. However, it remains unclear whether similar pathways operate in vivo. Here we found that antigen-specific T reg cells activated by dendritic cells (DCs) pulsed with two antigens suppressed conventional naive T cells (T naive cells) specific for both cognate antigens and non-cognate antigens in vitro but suppressed only T naive cells specific for cognate antigen in vivo. Antigen-specific T reg cells formed strong interactions with DCs, resulting in selective inhibition of the binding of T naive cells to cognate antigen yet allowing bystander T naive cell access. Strong binding resulted in the removal of the complex of cognate peptide and major histocompatibility complex class II (pMHCII) from the DC surface, reducing the capacity of DCs to present antigen. The enhanced binding of T reg cells to DCs, coupled with their capacity to deplete pMHCII, represents a novel pathway for T reg cell–mediated suppression and may be a mechanism by which T reg cells maintain immune homeostasis. Regulatory T cells suppress target cells through diverse mechanisms. Shevach and colleagues demonstrate that regulatory T cells in vivo strip complexes of cognate peptide and major histocompatibility complex class II from dendritic cells and thereby help to maintain immune homeostasis.