Abstract
Activation of the immune system increases systemic adrenal-derived glucocorticoid (GC) levels which downregulate the immune response as part of a negative feedback loop. While CD4+ T cells are essential target cells affected by GC, it is not known whether these hormones exert their major effects on CD4+ helper T cells, CD4+Foxp3+ regulatory T cells (Treg cells), or both. Here, we generated mice with a specific deletion of the glucocorticoid receptor (GR) in Foxp3+ Treg cells. Remarkably, while basal Treg cell characteristics and in vitro suppression capacity were unchanged, Treg cells lacking the GR did not prevent the induction of inflammatory bowel disease in an in vivo mouse model. Under inflammatory conditions, GR-deficient Treg cells acquired Th1-like characteristics and expressed IFN-gamma, but not IL-17, and failed to inhibit pro-inflammatory CD4+ T cell expansion in situ. These findings reveal that the GR is critical for Foxp3+ Treg cell function and suggest that endogenous GC prevent Treg cell plasticity toward a Th1-like Treg cell phenotype in experimental colitis. When equally active in humans, a rationale is provided to develop GC-mimicking therapeutic strategies which specifically target Foxp3+ Treg cells for the treatment of inflammatory bowel disease.
Highlights
Regulatory T cells (Treg cells) expressing the transcription factor Foxp3 maintain immune homeostasis by limiting antigen-specific immune responses and sustaining tolerance to self-antigens [1]
Quantification of the glucocorticoid receptor (GR) in conventional CD4+CD25− Foxp3− T cells, CD8+ T cells and B cells revealed no differences between wild type (WT), Foxp3-Cre and Foxp3-Cre GRfl/fl mice (Figure S1B), ruling out promiscuous Foxp3-Cre expression in these lymphocyte subsets
Supporting the view that GC, at least under basal conditions, do not influence Treg cell homeostasis are the results of the competitive experiments in heterozygous female Foxp3-Cre/wt GRfl/fl mice, clearly showing that in a physiologically normal environment no differences were observed in development and/or survival between WT and GR-deficient Treg cells
Summary
Regulatory T cells (Treg cells) expressing the transcription factor Foxp maintain immune homeostasis by limiting antigen-specific immune responses and sustaining tolerance to self-antigens [1]. Treg cell function is not mediated by one single common pathway, as many different mechanisms have been described including downregulation of costimulatory molecules (CD80/CD86) on dendritic cells, secretion of inhibitory cytokines or metabolic disruption of target cells. Some Treg cells may lose Foxp expression in autoimmune disease (“ex-Foxp3” cells), others, while maintaining Foxp expression, acquire a certain degree of plasticity which is illustrated by secretion of pro-inflammatory cytokines and reduced suppressive function [4]. The molecular mechanisms that drive Treg cell plasticity as well as the functional consequences for autoimmune diseases are largely unknown
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