Abstract
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.
Highlights
CD4+ CD127lowCD25+ regulatory T cells (Tregs), the majority of which differentiate in, and egress from, the thymus are an immune subset with a critical role in the maintenance of self-tolerance and protection against tissue damage and autoimmunity [1]
These data indicate that IL-6Rhi TIGIT− Tregs will be highly sensitive to the endogenous production of IL-2 induced by infection or inflammation, thereby stimulating the recruitment of these highly suppressive Tregs, which we suggest could be normally resident in the intestine and mesenteric lymph nodes, to sites of infected cells or inflammation, where these Tregs curtail effector activities and prevent potentially pathogenic tissue damage
We acknowledge the limitation of defining Tregs with the use of surface markers and the fact that human CD4+ CD127lowCD25+ T cells represent a heterogeneous population containing a subset of activated T effector cells (Teff) cells, for consistency, we here refer to CD4+ CD127lowCD25+ T cells as ‘Tregs’, as these represent the canonical surface markers used for the isolation of human Tregs for functional studies requiring viable cells
Summary
CD4+ CD127lowCD25+ regulatory T cells (Tregs), the majority of which differentiate in, and egress from, the thymus are an immune subset with a critical role in the maintenance of self-tolerance and protection against tissue damage and autoimmunity [1]. This Treg subset is defined by the expression of the transcription factor FOXP3, which is essential for their differentiation, maintenance and function [2]. FOXP3, along with other transcription factors, suppresses the expression of the IL-2 gene in these Tregs [2,4], making them critically dependent on IL-2 production from conventional or effector T cells (Teffs).
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