Regulatory T cells perform antigen specific suppression by depleting cognate peptide-MHC class II via trogocytosis

Abstract

Abstract Tregs are professional suppressors of the immune response, yet their mechanism of action in vivo remains unclear. Using electron microscopy and dynamic intravital two-photon microscopy, we revealed that unlike effector T cells, Tregs displayed a distinct morphology with membrane projections that resemble filopodia at the DC binding site increasing the surface area of the contact dramatically. Despite the intense contact with DC, Tregs only abolished the interactions of effector T cells with DC when the effectors shared the same antigen specificity with Tregs. However, this cessation of the effector T cell interactions was not due to a physical hindrance created by the superior binding ability of Treg since the antigen specific inhibition of T cell-DC interaction was still observed after Tregs are removed from the environment. Instead, the antigen-specific inhibition was secondary to the removal of cognate peptide-MHC Class II (pMHCII) from the surface of DC as evidenced by the strictly antigen-specific depletion of the pMHCII from double antigen pulsed DC. pMHCII capture was only performed by antigen specific Treg, not by polyclonal Treg and it was not secondary to the interaction of CTLA-4 with B7 molecules suggesting the functional importance of TCR in Treg suppression. Prominent members of the B7 family, that are not de novo expressed in Tregs, such as CD86, ICOSL and PD-L2 were acquired alongside the TCR, suggestive of a process that includes a membrane transfer event called trogocytosis. Altogether, we propose antigen specific depletion of peptide-MHCII complexes via trogocytosis as a new mechanism for Treg-mediated suppression.