Deciphering the regulation of tissue adaptation of regulatory T cells

Abstract

Regulatory T (Treg) cells are specialised immune cells of the CD4⁺ T cell lineage that are indispensable for the maintenance of immune homeostasis and prevention of immune-mediated pathology. Most Treg cells develop in the thymus and undergo a distinct differentiation program in the periphery, which is essential for the acquisition of a fully suppressive effector phenotype. This process endows Treg cells with the ability to migrate to multiple non-lymphoid tissues, where they mature and acquire tissue-specific features. Notably, tissue-resident Treg cells perform multiple non-immune functions, including the maintenance of tissue integrity and repair, as well as the regulation of systemic metabolism. In this study, we investigated the molecular control of tissue-specific effector Treg cell adaptation, focusing on two non-lymphoid tissues, the central nervous system (CNS) and adipose tissue. <br /> The CNS, composed of the brain and spinal cord, is responsible for reception, processing, and reaction to sensory stimuli. Recent studies have revealed the presence of immune cells, including Treg cells, in the CNS. However, the role of Treg cells in chronic CNS diseases, such as Multiple Sclerosis, remains poorly understood. In this study, we employed a mouse model of experimental autoimmune encephalomyelitis, recapitulating human Multiple Sclerosis, to investigate the effects of hypoxia-inducible factor 1-alpha (Hif1a) on Treg cells during disease progression. Hif1a, a transcription factor induced by hypoxia and inflammation, is elevated in Multiple Sclerosis patients. Independently, it has been shown to attenuate Treg cell development and function. My findings indicate that Treg cells that lack Hif1a switch to mitochondrial respiration at sites of inflammation. This change may enhance their effector function, which could have contributed to the alleviation of disease progression in female mice. <br /> Visceral adipose tissue (VAT) functions as an endocrine organ vital for metabolic homeostasis and energy storage. However, excessive accumulation of white adipose tissue due to aging or diet triggers tissue inflammation, increasing the risk of metabolic disorders, such as type 2 diabetes. Given the global obesity rise, understanding the interaction of the immune system with VAT is essential. Treg cells are critical for dampening VAT inflammation preserving tissue homeostasis and systemic metabolism. Research, including our own, indicates that a heterogeneous population of Treg cells accumulates in the VAT in a sex-dependent manner under steady-state conditions. These Treg cells can be categorised into two main clusters based on their expression of the interleukin (IL)-33 receptor ST2 and the chemokine receptor CXCR3. In male animals, prototypical ST2⁺ Treg cells, which depend on the transcription factors PPAR? and GATA3, are predominant. Conversely, CXCR3⁺ Treg cells, which rely on the transcription factor T-bet, are enriched in female mice. In addition to distinct phenotypical and functional characteristics, this study revealed differences in the metabolic requirements of these Treg cell populations showing elevated usage of amino acid metabolism in ST2⁺ Treg cells, while CXCR3⁺ Treg cells utilised mitochondrial respiration to maintain their high proliferative capacity. <br /> Furthermore, this study utilised novel transgenic mouse models, dietary conditions, and in vitro assays to investigate VAT microenvironmental signals that shape Treg cell differentiation, heterogeneity, and function. Our results identified a pivotal role for transforming growth factor-beta (TGF-ß) in maintaining VAT Treg cell homeostasis. Ablation of TGF-ß signalling in Treg cells favoured the expansion of CXCR3⁺ VAT Treg cells while reducing their overall sensitivity to IL-33 by the loss of ST2 expression. Phenotypic and functional changes in Treg cells in turn reshaped the cellular composition of VAT, creating an anti-inflammatory environment that prevented fat accumulation, even under high fat diet. Together, these results highlight a novel pathway by which TGF-ß steers VAT Treg cell differentiation and function, thereby contributing to the maintenance of VAT immune homeostasis and tissue morphology. Therefore, manipulation of Treg cells via TGF-ß may constitute a new, promising therapeutic target for metabolic diseases.