ABSTRACT
Inflammation is an important defense mechanism. In this complex and dynamic process, drastic changes in the tissue micro-environment play key roles in dictating the nature of the evolving immune response. However, uncontrolled inflammation is detrimental, leading to unwanted cellular damage, loss of physiological functions, and even death. As such, the immune system possesses tools to limit inflammation while ensuring rapid and effective clearance of the inflammatory trigger. Foxp3+ regulatory T (TREG ) cells, a potently immunosuppressive CD4+ T cell subset, play a crucial role in immune tolerance by controlling the extent of the response to self and non-self Ags, all-the-while promoting a quick return to immune homeostasis. TREG cells adapt to changes in the local micro-environment enabling them to migrate, proliferate, survive, differentiate, and tailor their suppressive ability at inflamed sites. Several inflammation-associated factors can impact TREG cell functional adaptation in situ including locally released alarmins, oxygen availability, tissue acidity and osmolarity and nutrient availability. Here, we review some of these key signals and pathways that control the adaptation of TREG cell function in inflammatory settings.
Subject(s)
Disease Susceptibility , Inflammation/etiology , Inflammation/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Adaptation, Biological , Alarmins/metabolism , Animals , Biomarkers , Cytokines/metabolism , Energy Metabolism , Environment , Humans , Inflammation/pathology , Stress, PhysiologicalABSTRACT
Regulatory T (Treg) cells integrate diverse environmental signals to modulate their function for optimal suppression. Translational regulation represents a favorable mechanism for Treg cell environmental sensing and adaptation. In this study, we carry out an unbiased screen of the Treg cell translatome and identify serum/glucocorticoid-regulated kinase 1 (SGK1), a known salt sensor in T cells, as being preferentially translated in activated Treg cells. We show that high salt (HS) drives thymic Treg cells to adopt a T helper type 17 (Th17)-like phenotype and enhances generation of Th17-like induced Treg cells in a SGK1-dependent manner, all the while maintaining suppressive function. Salt-mediated Th17-like differentiation of Treg cells was evident in mice fed with HS diet or injected with HS-preconditioned T cells. Overall, SGK1 enables Treg cells to adapt their function in response to environmental cues. By understanding these environmental-sensing mechanisms, we envision targeted approaches to fine-tune Treg cell function for better control of inflammation.
