Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune demyelinating diseases of the central nervous system (CNS). Interferon-gamma-producing Th1 and interleukin-17-producing Th17 CD4(+) T helper (Th) cells mediate disease pathogenesis in EAE and likely in MS as well. However, the relative contribution of each Th subset to autoimmune processes in the CNS remains unclear. Emerging data suggest that both Th1 and Th17 cells contribute to CNS autoimmunity, albeit through different mechanisms. A better understanding of the roles that Th1 and Th17 cells play in autoimmune inflammation will be helpful in developing new therapeutic approaches. In this review, we discuss recent findings on the roles of Th1 and Th17 cells in the pathogenesis of EAE.

Fig. 1

Differentiation of effector T helper subsets. After activation by professional antigen-presenting cells, naïve CD4⁺ T cells differentiate toward Th1 cells in the presence of IL-12. Th1 cells upregulate IFN-γ via Stat4, leading to IFN-γ-mediated Stat1 activation and induction of the Th1 lineage transcription factor T-bet. Th2 cells differentiate in response to IL-4, which activates Stat6, resulting in induction of GATA3. Th17 cell subset develops in response to IL-6 or IL-21 and TGFβ. This differentiation is enhanced in the presence of IL-1β and TNFα. IL-6 activates Stat3 and the lineage-determining transcription factors RORγt and RORα. Th17 differentiation is strongly inhibited by IFN-γ, IL-4, IL-27, IL-2, and IL-35. In addition, IL-17 inhibits Th1 polarization, expression of IFN-γ, and the transcription factor T-bet (O'Connor et al. 2009)

Fig. 2

CCR6–CCL20-dependent entry of Th17 cells into the CNS. CCR6⁺ Th17 cells interact with CCL20 expressed by the epithelium of the choroid plexus and enter the CNS. After reactivation with resident antigen-presenting cells and myelin antigens, CCR6⁺ Th17 cells secrete several cytokines and chemokines that initiate inflammation by modifying BBB permeability and attracting other immune cells. Further infiltration of various leucocytes, including Th1 cells, Th17 cells, granulocytes, and macrophages, amplifies the inflammation process that mediates destruction of the myelin sheath