Th17 Differentiation: An Evolving Target for Multiple Sclerosis Therapy

A growing body of evidence suggests a pathogenic role for T helper 17 cells (Th17) in several autoim­mune diseases, including multiple sclerosis (MS). Th17 cells differentiate from naïve CD4+ lymphocytes in the presence of IL-6 and TGF-beta.1 Differentiation of Th17 cells also requires IL-21 for amplification of Th17 precursors, and IL-23 for stabilization and terminal differentiation of Th17 cell populations.2, 3 Differentiated Th17 cells are characterized by the production of proinflammatory cytokines including IL-17A (IL-17), IL-17F, IL-21, and IL-22. It is generally accepted that the STAT3, RORgamma t , and RORalpha transcription factors are essential for Th17 cell differentiation, but how their activities are regulated is not completely understood.

Prolonged production of IL-17 by Th17 cells is dependent on the transcription factor Batf.
View Larger Image 		Prolonged production of IL-17 by Th17 cells is dependent on the transcription factor Batf. Recent studies suggest that prolonged production of IL-17 by Th17 cells is dependent on the synergistic actions of the RORgt and Batf-JunB transcription factors. These findings may have implications for Th17-related autoimmune disorders such as multiple sclerosis. Following induction of autoimmune conditions in mice using myelin oligodendrocyte glycoprotein (MOG) immunization, differentiated Th17 cells secrete proinflammatory cytokines, and activated macrophages destroy myelin and damage oligodendrocytes. It remains to be determined whether the induction of Batf expression is dependent on STAT3 in Th17 cells, and whether an interaction between Batf and Irf4 or Ahr is required to promote the respective induction of IL-21 and IL-22.

A recent study by Schraml and colleagues investigated the contribution of the AP-1 B cell-activating transcription factor (Batf) to T cell differentiation.4 In these studies, Batf-/- mice were shown to have normally differentiated Th1 and Th2 cells, but lacked differentiated Th17 cells. When stimulated toward a Th17 lineage in vitro, Batf-/- T cells produced normal levels of IL-2, IFN-gamma, and IL-10, but significantly reduced levels of IL-17. To test the hypothesis that Batf is a critical factor for IL-17 driven autoimmune disease, the authors attempted to induce experimental autoimmune encephalomyelitis (EAE) in Batf-/- mice. EAE is a mouse model of multiple sclerosis in which demyelinating autoimmune conditions are induced following immunization with myelin oligodendrocyte glycoprotein (MOG). Consistent with an underlying pathogenic role for IL-17, Batf-/- mice were completely resistant to the development of EAE.

A previous study found that IL-6 knockout mice were resistant to the development of EAE due to a compensatory increase in anti-inflam­matory FOXP3+ T regulatory (Treg) cells.5 However, no changes in FOXP3 expression were observed following immunization with MOG in Batf -/- mice, suggesting that the protective effect associated with a lo ss of Batf was not dependent on a compensatory increase in Treg cells. To ensure that EAE resistance was not caused by a non-specific T cell defect, Batf+/+ naïve CD4+ T cells were adoptively transferred into Batf-/- mice prior to MOG administration.4 Under these conditions, Batf-/- mice were no longer resistant to EAE, further supporting the involvement of Batf-dependent signaling in EAE development.

Using retroviral expression, Schraml et al. unveiled a synergistic relationship between RORgamma t and Batf in the production of IL-17.4 Further studies showed that although early induction of RORgamma t and RORalpha was normal in Batf-/- T cells, Batf was required to maintain the prolonged increase in RORgamma t and RORalpha expression observed in wild-type cells. The authors also demonstrated that Batf preferentially forms a heterodimer with JunB in Th17 cells, and this complex binds to the promoter regions of IL-17, IL-21, and IL-22 to positively regulate expression. Collectively, data from these experiments suggest that Batf is an essential factor for the differentiation of Th17 cells and the production of IL-17. Successful therapies for autoimmune disease must specifically inhibit pathological inflammation without inducing generalized immuno­suppression. The most commonly prescribed treatment for MS is IFN-beta, although this approach is only moderately effective, atten­uating disease conditions by approximately 35%.6 Using the EAE mouse model, two recent studies demonstrated that the underlying mechanism of IFN-beta action is dependent on antigen-presenting cells secreting IL-27.7, 8 IL-27 promotes the production of IL-10 which expands Treg populations and inhibits Th17 differentiation. Consistent with these observations, a dichotomy in the generation of Treg and Th17 cells has been previously reported.9 Further supporting Th17 cells as a direct pharmacological target, treatment with the small molecule halo­fuginone selectively inhibited Th17 cell differentiation and prevented EAE.10 Encouragingly, positive findings from EAE studies may also translate to other autoimmune diseases. For example, a selective EP4 prostaglandin receptor antagonist inhibited Th17 cell expansion and suppressed disease progression in models of both EAE and contact hypersensitivity (CHS).11

References

  1. Bettelli, E. et al. (2008) Nature 453:1051.
  2. Nurieva, R. et al. (2007) Nature 448:480.
  3. McGeachy, M.J. et al. (2009) Nat. Immunol. 10:314.
  4. Schraml, B.U. et al. (2009) Nature 460:405.
  5. Korn, T. et al. (2007) Nature 448:484.
  6. Tourbah, A. & O. Lyon-Caen (2007) Biochimie 89:899.
  7. Guo, B. et al. (2008) J. Clin. Invest. 118:1680.
  8. Prinz, M. et al. (2008) Immunity 28:675.
  9. Bettelli, E. et al. (2006) Nature 441:235.
  10. Sundrud, M.S. et al. (2009) Science 324:1334.
  11. Yao, C. et al. (2009) Nat. Med. 15:633.

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