In general, all the proposed mechanisms for Treg function postulate that once Tregs are activated via the TCR, the suppressor-effector mechanism they utilize is non-specific. We addressed this question by asking whether induced antigen-specific Tregs( iTregs) specific for one antigen could suppress the activation/expansion of naive T cells specific for a distinct antigen when both were simultaneously expressed by the same DCs. iTregs specific for one antigen suppressed the activation of naive T cells specific for their cognate antigen, but had no effect on the activation of naive T cells specific for a different antigen expressed on the same DC. We therefore explored alternative mechanisms by which iTregs might mediate suppressor function. We first compared the interaction of antigen-specific 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 naive 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.

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Akkaya, Billur; Holstein, Amanda H; Isaac, Christopher et al. (2017) Ex-vivo iTreg differentiation revisited: Convenient alternatives to existing strategies. J Immunol Methods 441:67-71
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