T cells in multiple sclerosis and experimental autoimmune encephalomyelitis

Abstract

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

Fig. 1

The differentiation and regulation of CD4⁺ T cell subsets. Naive T cells primed by antigen-presenting cells (APC) such as dendritic cells (DC) can differentiate into T regulatory-1 (Tr1)/T helper type 3 (Th3), Th1, Th2 or Th17 cells depending upon the cytokine environment. Priming in the presence of interleukin (IL)-10/transforming growth factor (TGF)-β, IL-12, IL-4 or combinations of IL-6/IL-1/IL-23 promotes the differentiation of Tr1/Th3, Th1, Th2 or Th17 cells, respectively [113]. Th17 cells can be regulated negatively by Th1 or Th2 cells. Tr1 and Th3 cells secrete IL-10 and TGF-β which can suppress effector cell responses, primarily by suppressing APC function. Natural regulatory T cells (T_reg) cells are derived from the thymus (although they may also be converted in the periphery) and can suppress effector T cell responses directly or via the APC [72].

Fig. 2

Migration and effector function of T cells in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). After immunization with myelin antigens, complete Freund's adjuvant (CFA) and pertussis toxin, dendritic cells (DC) are activated in the lymph nodes by Toll-like receptor (TLR) agonists within the mycobacterium tuberculosis component of CFA, and present myelin antigen to naive T cells. The activated myelin-specific T cells enter the bloodstream and traffic to and enter the CNS. Breakdown of the blood–brain barrier (BBB) occurs, allowing recruitment of other inflammatory cells into the CNS. T cells entering the CNS encounter their cognate myelin antigens and become reactivated by local APC. T cells expand and release inflammatory mediators which help recruit other immune cells to the site of inflammation. Activation of local microglial cells and infiltrating cells results in production of proteases, glutamate, reactive oxygen species and other cytotoxic agents which promote myelin breakdown. Damage to the myelin sheath surrounding axons is followed by axonal damage and neurological impairment.