T Helper 17 Cells And Mutiple Sclerosis

CD4+ T cells, based on cytokine production, were classically categorized into two subsets: T helper type 1 (Th1) and type 2 (Th2) cells. Th1 cells produce mainly interferon-γ, induce delayed hypersensitivity reactions,activate macrophages, and are essential for the defense against intracellular pathogens. Th2 cells produce mainly interleukin-4 and are important in inducing IgE production, recruiting eosinophils to sites of inflammation and helping to clear parasitic infections. More recently, a new subset of T cells was discovered that produce interleukin-17, but not interferon-γor interleukin-4, named Th17 cells.Th17 cells play an important role in inducing inflammation,clearing extracellular pathogens,autoimmune diseases,tumor and so on.The discovery of T helper 17 cells was based on the researches of EAE (experimental autoimmune encephalomyelitis) and CIA (collagen-induced arthritis), in which were previously believed that Th1 cells were pathogenic T cells .Th1 cells were induced by IL-12.Blocking IL-12 signaling was expected to ameliorate EAE. IL-12 is a heterodimeric cytokine composed of p35 and p40 subunit. However, it was shown that p35-deficient mice were susceptible, but p40-deficient mice were resistant to EAE. IL-23 is a heterodimeric cytokine that shares IL-12p40 subunit with IL-12 and possesses a unique p19 subunit. They demonstrated that IL-23p19 and IL-12p40, but not IL-12p35, were essential for the development of EAE.Researching the mechanism underlying the essential role of IL-23 has revealed that CD4+ T cells producing IL-17 were not induced in IL-23-deficient mice in EAE and CIA. This demonstrates that producing IL-17 cells rather than Th1 cells are important for the development of EAE and CIA. In 2005, Harrington identified these producing IL-17 cells as T helper 17 cells, a new linage of CD4+ T cells, based on cytokine production. Th17 cells were a distinct linage cells from Th1 and Th2 cells in differentiation.Interferon-γdrives naive T cells into the Th1 pathway, whereas interleukin-4 initiates the differentiation of naive T cells into Th2 cells。It has been shown that a combination of transforming growth factor-β(TGF-β) and IL-6 induces the differentiation of Th17 cells. Although IL-23 plays no apparent role in Th17 lineage commitment, it seems to be required for promoting, survival and proliferation of these cells. IL-21 amplifies th17 pathway in autocrine fashion.CD4+ T cell lineage commitment is regulated by specific transcription factors. Namely, Th1 differentiation requires STAT1, STAT4, and T-bet, whereas STAT6, c-maf, and GATA-3 act to promote Th2 cytokine production. Regarding to Th17 cell differentiation,retinoic acid-related orphan nuclear receptorγt (RORγt) is the key transcription factor that orchestrates the differentiation of Th17 cell lineage.At the same time RORα和STAT3, are also an essential transcription factor in Th17 cell differentiationTh17 cells can produce several cytokines,such as IL-17A,IL-17F,IL-22,IL-21 and so on.IL-17 now referred to as IL-17A, is the founding member of the IL-17 family, which includes IL-17A to F. IL-17 is the main effctor of th17cells. IL-17 has an important function as an inflammatory mediator.It can increase IL-6 and other proinflammatory cytokine production from a variety of cell types,induce and strengthen the immune response. It coordinates the recruitment of myeloid cells like monocytes and neutrophils to the site of an inflammation, thereby furthering the local inflammatory environment. This suggested that IL-17 can have a critical role in inflammatory conditions in general.Multiple sclerosis (MS) is a CD4+ T cell-mediated demyelinating disease affecting the central nervous system. It was largely accepted that Th1 cells were pathogenic T cells in human MS and experimental autoimmune encephalomyelitis, an animal model of MS. However,IFNγknockout mice surprisingly showed more severe EAE. Anti-IFNγtherapy induced severe EAE too. This suggested that there was another linage of CD4+ T cells besides Th1 cells,inducing autoimmune reaction. Moreover, interferonγ(IFNγ) induction pathway constrains Th17-mediated CNS autoimmune inflammation in mice. Genetic deficiency of IL-17 or neutralization of IL-17 in mice with EAE leads to amelioration of the clinical disease symptoms,but not to complete reduction. This has established that Th17 cells play a pivotal role in the pathogenesis of EAE. In patients with multiple sclerosis in whom lesions are restricted to the optic nerves and spinal cord, the levels of interleukin-17 in serum and cerebrospinal fluid are higher than in conventional multiple sclerosis, and the level of interleukin-17 in the cerebrospinal fluid correlates with the extent of spinal lesions as measured by means of magnetic resonance imaging.The function of Th17 cells in multiple sclerosis remains to be elucidated. It is demonstrated recently that auto reactive T cells identify myelin as special antigen,cross the blood-brain barrier and trigger the disease. There are expressions of IL-17 and IL-22 receptors on blood-brain barrier endothelial cells (BBB-ECs) in multiple sclerosis lesions, IL-17 and IL-22 disrupt BBB tight junctions. Furthermore, T(H)17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment.Recently researches in treatment of EAE or MS tageting in th17 pathway are under way. It has been demonstrated that: vitamin A metabolite retinoic acid as a key regulator of TGF-b–dependent immune responses, capable of inhibiting the IL-6–driven induction of proinflammatory TH17 cells and promoting anti-inflammatory Treg cell differentiation.Statin exerts an independent immunomodulatory effect on the human monocytes and CD4+ T cells. In addition to the statin-mediated effect on the monocyte cytokine production, which regulates Th17 cell differentiation, statin directly inhibits the autoimmune response in multiple sclerosis.Th17 cells are a distinct effector cell linage different from the Th1 cells and Th2 cells,which play an important role in the induction and development of MS and EAE. The discovery of this new immunal regulation pathway, based on th17 cells, provides a new direction of the researches focus on the mechanisms and treatments of autoimmune diseases specially MS.