T cell suppression by naturally occurring HLA-G-expressing regulatory CD4+ T cells is IL-10-dependent and reversible

HLA‐Gpos Treg‐mediated suppression is critically dependent on the secretion of IL‐10 but not TGF‐β. CD4+ T cells constitutively expressing the immune‐tolerogenic HLA‐G have been described recently as a new type of nTreg (HLA‐Gpos Treg) in humans. HLA‐Gpos Treg accumulate at sites of inflammation and are potent suppressors of T cell proliferation in vitro, suggesting their role in immune regulation. We here characterize the mechanism of how CD4+ HLA‐Gpos Treg influence autologous HLA‐Gneg Tresp function. Using a suppression system free of APC, we demonstrate a T–T cell interaction, resulting in suppression of HLA‐Gneg Tresp, which is facilitated by TCR engagement on HLA‐Gpos Treg. Suppression is independent of cell–cell contact and is reversible, as the removal of HLA‐Gpos Treg from the established coculture restored the proliferative capability of responder cells. Further, HLA‐Gpos Treg‐mediated suppression critically depends on the secretion of IL‐10 but not TGF‐β.