Human IL-6R(hi)TIGIT(-) CD4(+)CD127(low)CD25(+) T cells display potent in vitro suppressive capacity and a distinct Th17 profile

Abstract

To date many clinical studies aim to increase the number and/or fitness of CD4⁺CD127$^{low}$CD25⁺ 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⁺CD127$^{low}$CD25⁺ 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-6R$^{hi}$TIGIT⁺ Tregs. IL-6R$^{hi}$TIGIT⁻ CD127$^{low}$CD25⁺ 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⁺CD127$^{low}$CD25⁺ FOXP3⁺IL-6R$^{hi}$TIGIT⁻ T cells is temporarily disarmed allowing further activation of the effector functions and potential pathogenic tissue damage.This research was supported by the JDRF (9-2011-253/5-SRA-2015-130-A-N), the Wellcome Trust (WT091157/107212 and WT083650/Z/07/Z), the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, and the Cambridge Clinical Trials Unit (CCTU). RCF is funded by a JDRF advanced post-doctoral fellowship (3-APF-2015-88-A-N)