Abstract
BackgroundSema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS.MethodsWe adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-γ and IL-17A (n = 86), complete remission ratio by IFN-β (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study.ResultsSema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-γ levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-β unresponsiveness than those with low Sema4A levels.ConclusionsSema4A is involved not only in the Th cell priming but also in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in RRMS patients with high serum Sema4A levels.
Highlights
Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS)
Sema4A is involved in the Th cell priming and in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in relapsing-remitting multiple sclerosis (RRMS) patients with high serum Sema4A levels
Transferred Th17, but not Th1, encephalitogenic cells exacerbate EAE in Sema4Adeficient mice To confirm the relevance of Sema4A in EAE development, actively immunized EAE was induced in either wild type (WT) or Sema4A-deficient (Sema4A KO) mice
Summary
Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). The role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Some semaphorins are crucially involved in immune responses, including helper T cell (Th) activation and differentiation [5]. Sema4A is a membrane-type class IV semaphorin that we originally identified as a T cell regulator [6]. Recent studies suggest that Sema4A plays critical roles in many processes including immune cell activation, differentiation, and migration [7]. Sema4A is associated with carcinogenesis and retinal systems [8, 9]
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