Glucocorticoid Receptor-Deficient Foxp3+ Regulatory T Cells Fail to Control Experimental Inflammatory Bowel Disease

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.

Mechanisms of TREG cell adaptation to inflammation

“…While T REG cell adaptation at inflammatory sites is highly beneficial to the host, as uncontrolled inflammation may lead to increased localized and systemic damage, it can also be exploited by tumors to pro- inflammatory bowel disease, although it is not required for their suppressive ability. 133 Rapamycin, described as a potent Foxp3-inducing drug 134 and one of the most successful T REG modulatory drug, inhibits the mTOR pathway which in turn promotes OXPHOS over glycolysis and inhibits HIF-1 transcription, 135 suggesting that this drug can modify key components of T REG adaptation in order to "skew" them toward displaying their suppressive functions. Further investigation on the effect of these drugs on the environmental sensing ability of T REG cells will be key toward establishing a better rationale for their use.…”

The Complex Role of Regulatory T Cells in Immunity and Aging

“…Steroids and glucocorticoids can enlarge Treg populations in the periphery stimulating their function ( 111 ). In fact, Treg lacking the glucocorticoid receptor lose their suppressive function turning into Th1-like, IFNγ-producing cells in a murine colitis model ( 112 ).…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…GCs are well‐known for their general anti‐inflammatory effects, but beyond their production in adrenal glands, crypt IECs have been shown to release GCs in response to anti‐CD3‐mediated T‐cell activation, and IEC synthesis of GCs has been shown to control local inflammation and disease severity in a 2,4,6‐trinitrobenzene sulphonic acid colitis model . As almost all vertebrate cells express glucocorticoid receptors (GRs) the effects of GCs are pleiotropic; however, T‐cell‐specific responses to GCs have been shown to be involved in T‐cell homeostasis, and regulatory T (Treg) cell‐specific GR deficiency was recently shown to impair Treg cell capacity to prevent the induction of disease in a mouse model of inflammatory bowel disease . In addition, a recent study of mice with diminished GR responses revealed an interferon‐specific gene signature in the gut that was abrogated by antibiotic treatment, indicating a role for the microbiota .…”

“…76,77 As almost all vertebrate cells express glucocorticoid receptors (GRs) the effects of GCs are pleiotropic; however, T-cell-specific responses to GCs have been shown to be involved in T-cell homeostasis, and regulatory T (Treg) cell-specific GR deficiency was recently shown to impair Treg cell capacity to prevent the induction of disease in a mouse model of inflammatory bowel disease. 78,79 In addition, a recent study of mice with diminished GR responses revealed an interferon-specific gene signature in the gut that was abrogated by antibiotic treatment, indicating a role for the microbiota. 80 While information regarding intestinal production of GCs continues to emerge, the stimuli involved and immune cell effects have yet to be fully elucidated.…”