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IL-22 is a member of the IL-10 cytokine family involved in host protection against extracellular pathogens, by promoting epithelial cell regeneration and barrier functions. Dysregulation of IL-22 production has also frequently been observed in acute respiratory distress syndrome (ARDS) and several chronic inflammatory and autoimmune diseases. We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. Here we characterized the role of CD28 autonomous signaling in regulating IL-22 expression in human CD4 + T cells. We show that CD28 stimulation in the absence of TCR strongly up-regulates IL-22 gene expression and secretion. As recently observed for IL-17A, we also found that CD28-mediated regulation of IL-22 transcription requires the cooperative activities of both IL-6-activated STAT3 and RelA/NF-κB transcription factors. CD28-mediated IL-22 production also promotes the barrier functions of epithelial cells by inducing mucin and metalloproteases expression. Finally, by using specific inhibitory drugs, we also identified CD28-associated class 1A phosphatidylinositol 3-kinase (PI3K) as a pivotal mediator of CD28-mediated IL-22 expression and IL-22-dependent epithelial cell barrier functions., (Copyright © 2020 Kunkl, Amormino, Frascolla, Sambucci, De Bardi, Caristi, Arcieri, Battistini and Tuosto.)

As the Nobel laureate Luigi Pirandello wrote in his novels, identities can be evanescent. Although a quarter of a century has passed since regulatory T cells (Treg) were first described, new studies continue to reveal surprising and contradictory features of this lymphocyte subset. Treg cells are the core of the immunological workforce engaged in the restraint of autoimmune or inflammatory reactions, and their characterization has revealed substantial heterogeneity and complexity in the phenotype and gene expression profiles, proving them to be a most versatile and adaptive cell type, as exemplified by their plasticity in fine-tuning immune responses. Defects in Treg function are associated with several autoimmune diseases, including multiple sclerosis, which is caused by an inappropriate immune reaction toward brain components; conversely, the beneficial effects of immunomodulating therapies on disease progression have been shown to partly act upon the biology of these cells. Both in animals and in humans the pool of circulating Treg cells is a mixture of natural (nTregs) and peripherally-induced Treg (pTregs). Particularly in humans, circulating Treg cells can be phenotypically subdivided into different subpopulations, which so far are not well-characterized, particularly in the context of autoimmunity. Recently, Treg cells have been rediscovered as mediators of tissue healing, and have also shown to be involved in organ homeostasis. Moreover, stability of the Treg lineage has recently been addressed by several conflicting reports, and immune-suppressive abilities of these cells have been shown to be dynamically regulated, particularly in inflammatory conditions, adding further levels of complexity to the study of this cell subset. Finally, Treg cells exert their suppressive function through different mechanisms, some of which-such as their ectoenzymatic activity-are particularly relevant in CNS autoimmunity. Here, we will review the phenotypically and functionally discernible Treg cell subpopulations in health and in multiple sclerosis, touching also upon the effects on this cell type of immunomodulatory drugs used for the treatment of this disease., (Copyright © 2019 Sambucci, Gargano, Guerrera, Battistini and Borsellino.)

Fas and Fas Ligand (FasL) are two molecules involved in the regulation of cell death. Their interaction leads to apoptosis of thymocytes that fail to rearrange correctly their T cell receptor (TCR) genes and of those that recognize self-antigens, a process called negative selection; moreover, Fas-FasL interaction leads to activation-induced cell death, a form of apoptosis induced by repeated TCR stimulation, responsible for the peripheral deletion of activated T cells. Both control mechanisms are particularly relevant in the context of autoimmune diseases, such as multiple sclerosis (MS), where T cells exert an immune response against self-antigens. This concept is well demonstrated by the development of autoimmune diseases in mice and humans with defects in Fas or FasL. In recent years, several new aspects of T cell functions in MS have been elucidated, such as the pathogenic role of T helper (Th) 17 cells and the protective role of T regulatory (Treg) cells. Thus, in this review, we summarize the role of the Fas-FasL pathway, with particular focus on its involvement in MS. We then discuss recent advances concerning the role of Fas-FasL in regulating Th17 and Treg cells' functions, in the context of MS.