TGF-β regulation of encephalitogenic and regulatory T cells in multiple sclerosis

Abstract

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine that has been shown to influence the differentiation and function of T cells. The role that TGF-β plays in immune-mediated disease, such as multiple sclerosis (MS), has become a major area of investigation since CD4⁺ T cells appear to be a major mediator of autoimmunity. This review provides an analysis of the literature on the role that TGF-β plays in the generation and regulation of encephalitogenic and regulatory T cells (Treg) in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as well as in T cells of MS patients. Since TGF-β plays a major role in the development and function of both CD4⁺ effector and Treg, which are defective in MS patients, recent studies have found potential mechanisms to explain the basis for these T-cell defects to establish a foundation for potentially modulating TGF-β signaling to restore normal T-cell function in MS patients.

Keywords: Experimental autoimmune encephalomyelitis (EAE); Multiple sclerosis; T cells; TGF-β; miRNA.

Figure 1. TGF-β influences the differentiation of subsets of CD4 T cells

CD4 T cells can differentiate into several phenotypes. TGF-β in the presence of IL-6 promotes the differentiation of Th17 cells, but these cells are not highly encephalitogenic. TGF-β in the presence of IL-4 generated Th9 cells that have also been implicated in CNS autoimmunity, IL-9 can also have anti-inflammatory effects. TGF-β signaling is vital to the development and function of Tregs, which are necessary to prevent and control autoimmunity.

Figure 2. TGF-β negatively regulates naïve and effector CD4 T cells, but by distinct mechanisms

TGF-β inhibits the proliferation and differentiation of naïve CD4 T cells, even under Th1 cell polarizing conditions. In contrast, TGF-β enhances cytokine production and proliferation of effector Th1 cells, but also upregulated the anti-inflammatory cytokine IL-10. Thus, TGF-β also alters myelin-specific effector Th1 cells such that they are no longer encephalitogenic.

Figure 3. Naïve CD4 T cells of MS patients have dysregulated miRNA expression which target the TGF-β signaling pathway and suppress Treg development and function

Numerous miRNAs were found to be over-expressed in naïve CD4 T cells of MS patients that target TGF-βRI, TGF-βRII, SMAD2 and SMAD4. In contrast, 3 miRNA were down-regulated that were predicted to target SMAD7, a negative regulator of the TGF-β signaling pathway. Severin et al [78] found that these miRNAs reduced the ability of naïve CD4 T cells to differentiate into Tregs which may partially explain the Treg defect observed in MS patients.