Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells

Abstract Foxp3-expressing CD4+CD25+ regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and homeostasis. They constitutively highly express immune checkpoint receptor CTLA-4, whose Treg-specific deficiency causes severe systemic autoimmunity. As a key mechanism Treg-mediated suppression, CTLA-4 downregulates expression CD80/CD86 costimulatory ligands on antigen-presenting (APCs). Here we showed that facilitated synapse formation conjugation Tregs APCs. These conjugates thus provided stable platforms whereby were able to deplete proteins APCs by uptaking them via CTLA-4-dependent trogocytosis. The depletion occurred even with expressing mutant lacking cytoplasmic portion required for its endocytosis. trogocytosis also accelerated vitro vivo passive transfer other membrane lipid molecules from without their significant reduction APC surface. Furthermore, CD80 downregulation or blockade Treg-expressed solubilized form, respectively, disrupted cis-CD80/PD-L1 heterodimers increased free PD-L1 dendritic cells. Taken together, can exert dual suppressive effects T-cell responses converting stimulatory (CD80highfree PD-L1low) DCs non-stimulatory/inhibitory (CD80lowfree PD-L1high) Immune therapies combination anti-CTLA-4 anti-PD-1/PD-L1 antibodies may therefore synergistically hinder thereby effectively enhancing tumor immunity.