Abstract
The nuclear receptor Liver X Receptor (LXR) is a ligand-activated transcription factor that has been implicated in control of chronic inflammation by downregulating pro-inflammatory T cell responses. An impaired function of regulatory T cells, a subset of CD4+ T cells with a crucial role in maintaining lymphocytes homeostasis and immune regulation, is frequently observed in chronic inflammatory diseases. We observed that pharmacological activation of LXR in T cells not only resulted in a thorough suppression of Th1 and Th17 polarization in vitro, but also significantly induced regulatory T cells (Treg) cell differentiation in a receptor-specific fashion. In line with this, systemic LXR activation by oral treatment of mice with the LXR agonist GW3965 induced gut-associated regulatory T cells in vivo. Importantly, such LXR-activated Tregs had a higher suppressive capacity in functional in vitro coculture assays with effector T cells. Our data thus point towards a dual role of LXR-mediated control of inflammation by suppression of pro-inflammatory T cells and reciprocal induction of regulatory T cells.
Highlights
Regulatory T cells (Treg) are a subset of CD4+ T cells that play a key role in prevention of autoimmune diseases, maintainance of immune homeostasis and modulation of immune responses during infection [1]
To assess whether T cell differentiation is modulated by Liver X Receptor (LXR) activation, we in vitro differentiated CD4+ T cells with polarizing cytokines in the presence of TCR activation into either regulatory T cells (Treg) or pro-inflammatory Th1 and Th17 cells
Enhanced Treg differentiation was completely abrogated in LXRα/β-deficient T cells (Fig 1B), demonstrating that effects of GW3965 were receptor-specific
Summary
Regulatory T cells (Treg) are a subset of CD4+ T cells that play a key role in prevention of autoimmune diseases, maintainance of immune homeostasis and modulation of immune responses during infection [1]. Forkhead box P3 (FoxP3), the master transcription factor of Treg, is crucial for development of suppressive function [2, 3]. Besides expressing FoxP3, Treg are characterized by constitutive CD25 expression and low / absent CD127 expression [8,9,10,11]. CD25 is part of a high-affinity IL-2 receptor (IL-2R) and is essential for generation, expansion and suppressive capacity of Treg [12, 13]. FoxP3 induces high expression of CD25 as well as expression of CTLA-4, a Treg-associated surface molecule [14].
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