Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood–brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease.

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-kB 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.