Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis?

Abstract

Our understanding of the pathophysiology of multiple sclerosis (MS) has evolved significantly over the past two decades as the fields of immunology and neurobiology provide new avenues of exploration into the cause and mechanism of the disease. It has been known for decades that T cells have different cytokine phenotypes, yet the cytokine phenotype of pathogenic T cells in MS is still an area of debate. In EAE, it appears that IFNγ and IL-17, produced by Th1 and Th17 cells respectively, are not the critical factor that determines T cell encephalitogenicity. However, there are molecules such as IL-23, T-bet and STAT4, that appear to be critical, yet it is unclear whether all these molecules contribute to a common, yet undefined pathway, or act in a synergistic manner which culminates in encephalitogenicity has still to be determined. Therefore, the focus of research on effector T cells in MS should focus on pathways upstream of the cytokines that define Th1 and Th17 cells, since downstream products, such as IFNγ and IL-17, probably are not critical determinants of whether an effector T cells is capable of trafficking to the CNS and inducing inflammatory demyelination.

Figure 1. Th1 and Th17 cell differentiation and trafficking to the CNS

(A) Naïve CD4 T cells can differentiate into Th1 or Th17 cells. During Th17 cell differentiation, TGFβ can enhance IL-17 production, but this diminishes the capacity of these cells to induce EAE. (B) The distribution of Th1 and Th17 cells within the CNS various in EAE. Th1 cells home preferentially to the spinal cord, while Th17 cells appear to preferentially traffic to the brain. The number of Th1 cells in the CNS significantly outnumbers Th17 cells in myelin-immunized mice. (C) Transcriptional regulation of Th1 and Th17 differentiation lends insight into signaling pathways that may be important in the development of encephalitogenic T cells. T-bet is found encephalitogenic Th1 and Th17 cells. The presence of TGFβ during Th17 cell differentiation contributes to the inhibition of T-bet, resulting in non-encephalitogenic Th17 cells if primed with IL-6+TGFβ.

Figure 1. Th1 and Th17 cell differentiation and trafficking to the CNS

(A) Naïve CD4 T cells can differentiate into Th1 or Th17 cells. During Th17 cell differentiation, TGFβ can enhance IL-17 production, but this diminishes the capacity of these cells to induce EAE. (B) The distribution of Th1 and Th17 cells within the CNS various in EAE. Th1 cells home preferentially to the spinal cord, while Th17 cells appear to preferentially traffic to the brain. The number of Th1 cells in the CNS significantly outnumbers Th17 cells in myelin-immunized mice. (C) Transcriptional regulation of Th1 and Th17 differentiation lends insight into signaling pathways that may be important in the development of encephalitogenic T cells. T-bet is found encephalitogenic Th1 and Th17 cells. The presence of TGFβ during Th17 cell differentiation contributes to the inhibition of T-bet, resulting in non-encephalitogenic Th17 cells if primed with IL-6+TGFβ.