Human IL-6RhiTIGIT− CD4+ CD127lowCD25+ T cells display potent in vitro suppressive capacity and a distinct Th17 profile

•IL-6R is highly expressed in certain Treg subsets.•IL-6RhiTIGIT− CD127lowCD25+ T cells contain a subset of antigen-experienced Tregs with potent suppression capacity.•IL-6RhiTIGIT− Tregs display a Th17 transcriptional profile ex vivo, and the capacity to migrate to the gut.•IL-2 treatment in humans elicits the trafficking and expansion of Tregs in circulation.

To date many clinical studies aim to increase the number and/or fitness of CD4+ CD127lowCD25+ regulatory T cells (Tregs) in vivo to harness their regulatory potential in the context of treating autoimmune disease. Here, we sought to define the phenotype and function of Tregs expressing the highest levels of IL-6 receptor (IL-6R). We have identified a population of CD4+ CD127lowCD25+ TIGIT− T cells distinguished by their elevated IL-6R expression that lacked expression of HELIOS, showed higher CTLA-4 expression, and displayed increased suppressive capacity compared to IL-6RhiTIGIT+ Tregs. IL-6RhiTIGIT− CD127lowCD25+ T cells contained a majority of cells demethylated at FOXP3 and displayed a Th17 transcriptional signature, including RORC (RORγt) and the capacity of producing both pro- and anti-inflammatory cytokines, such as IL-17, IL-22 and IL-10. We propose that in vivo, in the presence of IL-6-associated inflammation, the suppressive function of CD4+ CD127lowCD25+ FOXP3+ IL-6RhiTIGIT− T cells is temporarily disarmed allowing further activation of the effector functions and potential pathogenic tissue damage.