Glucocorticoid Receptor-Deficient Foxp3+ Regulatory T Cells Fail to Control Experimental Inflammatory Bowel Disease
Lourdes Rocamora-Reverte1, Selma Tuzlak1, Laura von Raffay1
1Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck, Austria.
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.
Insights
Glucocorticoids are vital for regulatory T cell (Treg) function in preventing inflammatory bowel disease. Blocking the glucocorticoid receptor in Treg cells impairs their ability to control inflammation.
Area of Science:
- Immunology
- Endocrinology
- Gastroenterology
Background:
- Glucocorticoids (GC) downregulate immune responses via a negative feedback loop involving adrenal-derived hormones.
- CD4+ T cells are key targets of GC, but their specific effects on helper T cells versus regulatory T cells (Treg) remain unclear.
Purpose of the Study:
- To investigate the role of the glucocorticoid receptor (GR) in Foxp3+ Treg cells.
- To determine if GR signaling in Treg cells is essential for controlling experimental inflammatory bowel disease.
Main Methods:
- Generated mice with a specific deletion of the glucocorticoid receptor (GR) in Foxp3+ Treg cells.
- Assessed Treg cell characteristics and suppressive capacity *in vitro*.
- Evaluated the *in vivo* role of GR-deficient Treg cells in a mouse model of inflammatory bowel disease.
Main Results:
- Treg cells lacking the GR maintained normal basal characteristics and *in vitro* suppression.
- GR-deficient Treg cells failed to prevent the induction of experimental inflammatory bowel disease.
- Under inflammation, GR-deficient Treg cells adopted Th1-like characteristics (IFN-gamma expression) and could not inhibit pro-inflammatory CD4+ T cell expansion.
Conclusions:
- The glucocorticoid receptor is critical for the function of Foxp3+ Treg cells in controlling experimental colitis.
- Endogenous glucocorticoids prevent Treg cell plasticity towards a Th1-like phenotype during inflammation.
- Targeting the glucocorticoid receptor in Treg cells offers a potential therapeutic strategy for inflammatory bowel disease.
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