Environmental regulation of immune cell balance: mechanistic insights and disease implications

Abstract

Immune dysregulation dictates the development of a broad range of diseases from autoimmune disorders to cancers. Loss of immune balance refers to disruption between immunosuppression and activation. FOXP3+ regulatory T cells (Tregs), are crucial for maintaining immune tolerance and inhibition of excessive immune responses. Tregs adapt to the local environment through various mechanisms, including membrane bound cytokine receptors responsible for sensing and integrating environmental signals that shape their phenotype and function. Tregs also display unique metabolic requirements and their suppressive capacities strictly depend on oxidative phosphorylation (OXPHOS) in contrast to effector T cell depending mostly on glycolysis. In autoimmune diseases Tregs lose their stability and function and are often observed to acquire a pro-inflammatory phenotype called Th-1-like with enhanced production of IFNγ. Previous studies demonstrated that autoimmune Tregs exhibit diminished mitochondrial fitness with transcriptomic profile indicating immunometabolic reprogramming. Moreover, another study revealed that in eukaryotic cells OXPHOS is negatively regulated by influx of sodium into mitochondria under hypoxic conditions. Sodium has been described to affect different immune cell subsets, particularly Tregs leading to loss of suppressive functions. Moreover, sodium as a dietary factor has been shown to profoundly shape host immunity and disease either by directly acting on immune cells or by indirectly affecting the gut microbiota. While several dietary interventions have been tested in immune-regulated conditions such as autoimmunity and cancer, most have failed to establish causal impact. Similarly, the exact mechanism underlying diet impact on gut microbiome-immune axis and disease are still poorly understood and the number of studies investigating the impact of dietary patterns on immune regulation on the molecular level in detail are limited. There has been a significant increase in the incidence of autoimmune diseases like Multiple Sclerosis (MS) in the last decades which is most likely driven by a change in environmental factors. Understating these environmental factors and their interaction with immune system is essential for development of preventive and therapeutic strategies. This thesis investigated how environmental signals including elevated sodium concentration and low oxygen levels affects immune balance. In particular, how regulatory T cells adapt to changes in microenvironment by alteration of phenotype and metabolism. In addition, I reported how sodium influences immune responses by direct effect on Tregs and by interaction with gut microbiome. In the first part, I focused on the role of the common β-chain cytokine receptor CSF2RB and demonstrated its high expression linked to autoimmune Tregs. Next, I described how excessive sodium disrupts activity of electron transport chain (ETC), leading to Treg loss of function in vitro and in vivo. Further, I revealed that hypoxic conditions, often present in highly inflamed and/or ischemic tissue, induce similar immunometabolic reprogramming in Tregs, leading to increased IFNγ production and loss of suppressive functions. In addition, teriflunomide, a globally approved treatment for MS interfered with Treg mitochondrial fitness and reduced its capacities to inhibit effector T cells. Finally, I broadened the scope of high salt (HS), demonstrating that gut microbiota shaped by high salt diet (HSD) modulates immune responses, affecting immunosuppressive myeloid-derived suppressor cells (MDSCs), and enhancing anti-tumor responses. Together, the findings of this thesis provide new insights into the environmental factors that impair Treg function, highlighting a profound role of mitochondrial metabolism in maintaining immune tolerance. This research sheds new light on mechanisms which could be the basis for the development of therapeutic strategies aimed to restore immune balance and improve treatment outcomes in autoimmune and immune-related diseases.