Antigen-specific induced T regulatory cells (iTregs) inhibit dendritic cell (DC) function by capturing peptide-MHCII complexes from the DC surface

Abstract

Abstract Tregs are critical mediators of peripheral immune tolerance. A majority of the mechanisms utilized by antigen-specific Tregs to suppress immune responses, suggest an initial inhibition of dendritic cell (DC) function that results in diminished activation of T effector cells (Teff) specific for the homologous target as well as diminished activation of other antigen-specific Teff cells that recognize different antigens presented by the same DC (bystander suppression). In an adoptive transfer model in vivo, we demonstrated that OTII transgenic iTregs specific for Ovalbumin323–339 markedly inhibited the expansion of OTII Teff, but did not inhibit the expansion of co-transferred SMARTA Teff (specific for LCMV NP61–76) even though the transferred DCs displayed both peptides. Analysis of iTreg-DC co-cultures in vitro using flow cytometry and confocal microscopy demonstrated that specific peptide-MHCII complexes were captured and internalized by iTregs leaving DCs with decreased levels of antigen. Polyclonal iTregs, naïve, and activated antigen-specific Teff did not capture peptide-MHCII complexes. Intravital microscopy of the popliteal lymph node showed that adoptively transferred OTII iTregs made larger clusters around the DC for a longer period of time compared to activated Teff and increased the speed of co-transferred naïve OTII Teff cells. Taken together these studies suggest that antigen-specific iTregs inhibit immune responses locally in an antigen-dependent fashion by forming firm interactions with DCs leading to a stripping of peptide-MHCII complexes from the DC surface by a transendocytosis-based mechanism.