Unique interaction dynamics and peptide-MHC class II (pMHC II) transendocytosis lead to antigen-specific T regulatory cell (Treg)-mediated suppression

Abstract

Abstract Tregs can employ numerous mechanisms for inhibiting immune responses. Antigen-specific Tregs exhibit enhanced capacity to suppress compared to polyclonal Tregs, but unique suppressor mechanisms used by antigen-specific Tregs have not been elucidated. We first compared the interaction of antigen-specific induced Tregs (iTregs) and antigen-specific T effector cells with dendritic cells (DC) using scanning electron microscopy and intravital two-photon microscopy. Antigen-specific iTregs uniquely and rapidly formed dense clusters around DC suggesting that they may prevent the access of antigen-specific CD4+ T cells to the DC surface. In an adoptive transfer model, this rapid interaction was accompanied by a decreased ability of co-transferred naïve T cells to interact with the DCs as indicated by their failure to decrease their motility. More importantly, antigen-specific iTregs were found to specifically transendocytose cognate peptide-MHCII complexes from the DC surface to a greater extent than T effector cells resulting in diminished levels of antigen on the DC surface. Transmission electron microscopy of DC-Treg co-cultures showed that Tregs engulfed parts of DC processes as membrane invaginations within two hours and then internalized the p-MHCII complexes into endosomal vesicles. Taken together, these results indicate a two-step process by which antigen-specific Tregs inhibit antigen presentation. They rapidly and efficiently adhere to the DC surface and then deplete the pMHC II complexes from the DC resulting in potent suppression of the capacity of the DC to activate antigen-specific T cells.