Clorinda Fusco

The discovery of the transcription factor Forkhead box-p3 (Foxp3) has shed fundamental insights into the understanding of the molecular determinants leading to generation and maintenance of T regulatory (Treg) cells, a cell population with a key immunoregulatory role. Work over the past few years has shown that fine-tuned transcriptional and epigenetic events are required to ensure stable expression of Foxp3 in Treg cells. The equilibrium between phenotypic plasticity and stability of Treg cells is controlled at the molecular level by networks of transcription factors that bind regulatory sequences, such as enhancers and promoters, to regulate Foxp3 expression. Recent reports have suggested that specific modifications of DNA and histones are required for the establishment of the chromatin structure in conventional CD4+ T (Tconv) cells for their future differentiation into the Treg cell lineage. In this review, we discuss the molecular events that control Foxp3 gene expression and address the associated alterations observed in human diseases. Also, we explore how Foxp3 influences the gene expression programs in Treg cells and how unique properties of Treg-cell subsets are defined by other transcription factors.

Type 2 diabetes (T2D) is characterized by a progressive status of chronic, low-grade inflammation (LGI) that accompanies the whole trajectory of the disease, from its inception to complication development. Accumulating evidence is disclosing a long list of possible "triggers" of inflammatory responses, many of which are promoted by unhealthy lifestyle choices and advanced age. Diabetic patients show an altered number and function of immune cells, of both innate and acquired immunity. Reactive autoantibodies against islet antigens can be detected in a subpopulation of patients, while emerging data are also suggesting an altered function of specific T lymphocyte populations, including T regulatory (Treg) cells. These observations led to the hypothesis that part of the inflammatory response mounting in T2D is attributable to an autoimmune phenomenon. Here, we review recent data supporting this framework, with a specific focus on both tissue resident and circulating Treg populations. We also propose that selective interception (or expansion) of T cell subsets could be an alternative avenue to dampen inappropriate inflammatory responses without compromising immune responses.

Extracellular vesicles (EVs) are released by all cells and contribute to cell-to-cell communication. The capacity of EVs to target specific cells and to efficiently deliver a composite profile of functional molecules have led researchers around the world to hypothesize their potential as therapeutics. While studies of EV treatment in animal models are numerous, their actual clinical benefit in humans has more slowly started to be tested. In this scoping review, we searched PubMed and other databases up to 31 December 2023 and, starting from 13,567 records, we selected 40 pertinent published studies testing EVs as therapeutics in humans. The analysis of those 40 studies shows that they are all small pilot trials with a large heterogeneity in terms of administration route and target disease. Moreover, the absence of a placebo control in most of the studies, the predominant local application of EV formulations and the inconsistent administration dose metric still impede comparison across studies and firm conclusions about EV safety and efficacy. On the other hand, the recording of some promising outcomes strongly calls out for well-designed larger studies to test EVs as an alternative approach to treat human diseases with no or few therapeutic options.

FOXP3+CD4+ regulatory T cells (Tregs) are critical for immune homeostasis and respond to local tissue cues, which control their stability and function. We explored here whether developmental endothelial locus-1 (DEL-1), which, like Tregs, increases during resolution of inflammation, promotes Treg responses. DEL-1 enhanced Treg numbers and function at barrier sites (oral and lung mucosa). The underlying mechanism was dissected using mice lacking DEL-1 or expressing a point mutant thereof, or mice with T cell-specific deletion of the transcription factor RUNX1, identified by RNA sequencing analysis of the DEL-1-induced Treg transcriptome. Specifically, through interaction with αvβ3 integrin, DEL-1 promoted induction of RUNX1-dependent FOXP3 expression and conferred stability of FOXP3 expression upon Treg restimulation in the absence of exogenous TGF-β1. Consistently, DEL-1 enhanced the demethylation of the Treg-specific demethylated region (TSDR) in the mouse Foxp3 gene and the suppressive function of sorted induced Tregs. Similarly, DEL-1 increased RUNX1 and FOXP3 expression in human conventional T cells, promoting their conversion into induced Tregs with increased TSDR demethylation, enhanced stability, and suppressive activity. We thus uncovered a DEL-1/αvβ3/RUNX1 axis that promotes Treg responses at barrier sites and offers therapeutic options for modulating inflammatory/autoimmune disorders.