Glucocorticoids and regulatory T cells

The potency of glucocorticoids (GC) as negative regulators of immune and inflammatory effector molecules is widely accepted and as such they are successfully used in the treatment of autoimmune and inflammatory diseases. Less well understood are the effects of endogenous GC on T cell development, selection and function. Recent evidence suggests that GC are needed for a robust immune response. In particular, GC enable the selection of T cells in the thymus that express T cell receptors (TCRs) with sufficient affinity for MHCs, thereby ensuring their effector function in the periphery. In contrast, it is not clear how GC impact on development and function of the central T cell subset that secures peripheral tolerance to self, i.e. Foxp3+ regulatory T cells (Treg cells). If GC would affect selection of Treg cells analogous to their effects on selection of conventional T cells, we expect that the absence of GC results in a reduction of TCR affinity for self and, as a consequence, a compromised functional potency of Treg cells. We will address this question by generating mice with a specific deletion of the glucocorticoid receptor (GR) in Foxp3+ Treg cells (GRfl/fl x Foxp3YFP-Cre mice) to investigate whether the inhibitory potency of these Treg cells is indeed reduced. Conversely, a potential increase of Treg cell activity will be analyzed in mice that overexpress the GR in T cells (Lck-GR-Tg mice). The impact of either GR-deficiency or GR-overexpression on Treg cell function will also be addressed under inflammatory conditions in two in vivo model systems, experimental T cell transfer colitis in RAG1-/- mice and experimental autoimmune encephalomyelitis. We anticipate that this analysis will sharpen our understanding how GC exert their pleiotropic effects on immune cell function and may open new opportunities to increase the efficacy of GC treatment and/or dampen GC- dependent side effects during the treatment of autoimmune diseases.

In this FWF project, we investigated whether glucocorticoids (GC), which are a class of steroid hormones that are secreted in response to stress, influence the development of autoimmune diseases. The potency of GC as inhibitors of immune and inflammatory responses is widely accepted and as such they are successfully used in the clinic to treat autoimmune and inflammatory diseases. Less well understood are the effects of GC on T cell development and function. T cells are a critical part of the immune system and as such of great importance to i) detect invading pathogens and ii) mediate immune responses against these microbes. A small subset of T cells, so-called regulatory T cells (Treg cells), have an opposite function and prevent the immune system to attack and damage its own tissues, which occurs in autoimmune diseases such as inflammatory bowel disease. How GC influence the development and function of these Treg cells is subject of this project. We generated mice whose Treg cells are selectively deficient for the protein that is known to mediate the effects of GC in cells, the glucocorticoid receptor (GR). These cells are termed Treg-GR-deficient cells. The immune system of these mice appeared unchanged under basal conditions. However, in middle-aged mice, we detected an increased number of mice that had a positive blood test for a risk factor for developing autoimmune diseases, i.e. anti- nuclear antibodies (ANA). To test whether our mice would be more sensitive to develop an autoimmune disease, we used an experimentally-induced inflammatory bowel disease model. We found that Treg-GR-deficient cells had a strongly reduced function in this animal model. As a consequence, mice receiving Treg-GR-deficient cells developed inflammatory bowel disease whereas mice treated with normal Treg cells stayed healthy. Our findings indicate that GC affect Treg cells and strengthen their function. Since GC have numerous side-effects when used to treat autoimmune diseases, future therapies aiming to target GC specifically to Treg cells may be clinically effective, while simultaneously strongly reducing the adverse effects of these hormones.