Effector Th1 cells demonstrate self-regulation in a mouse model of Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) that is perpetuated by myelin-specific autoreactive CD4+ T cells. Interestingly, both healthy individuals and MS patients have myelin-specific T cells; however, these cells are of an effector-memory phenotype in MS patients, indicating previous exposure to antigen (Ag). Additional phenotypic analysis has demonstrated these cells are primarily of an effector-memory T helper (Th) 1 and Th17 lineage in MS patients. After activation in the periphery, myelin-specific T cells traffic to the CNS and enter a unique cytokine microenvironment that has the potential to influence the effector and/or regulatory mechanisms of these infiltrating cells. This project was initiated to determine how cytokines in the CNS microenvironment influence the pathogenicity of myelin-specific Th1 effector cells.;Transforming growth factor (TGF)-beta is a cytokine expressed in both the healthy and inflamed CNS with demonstrated suppressive effects on naive CD4+ T cell differentiation; however, the effects of this cytokine on Ag-experienced Th1 effector cells are not well defined. Using myelin-specific T cell receptor (TCR) transgenic (Tg) mice in the experimental autoimmune encephalomyelitis (EAE) model of MS, we demonstrate that TGF-beta elicits differential effects on proliferation, cellular activation, and cytokine secretion based on the differentiation state of a CD4+ T cell (i.e. naive versus effector-memory). Additionally, Th1 effector cells begin to produce IL-10 as a self-regulatory mechanism that is enhanced with both activation in an environment rich in TGF-beta, and repetitive Ag stimulation. TGF-beta signaling caused direct binding of smad4 to the IL-10 promoter, providing molecular evidence for TGF-beta-mediated regulation of IL-10 production in Th1 effector cells. Furthermore, the IL-10 produced by IFN-gamma +IL-10+ Th1 effector cells decreased EAE severity by reducing the expression of encephalitogenic markers on IL-10R+ cells and preventing host-cell recruitment to the inflamed CNS. These data establish a regulatory mechanism by which highly activated Th1 effector cells modulate their pathogenicity through induction of IL-10.;This work is a demonstration of the complex signaling networks that direct the functions of immune cells. Furthermore, the data presented highlight the importance of regulatory mechanisms that modulate the immune response, whether during normal inflammation or autoimmunity. In the context of MS, increasing the inherent regulatory potential of pathogenic effector-memory T cells may lead to novel therapies for the treatment of this debilitating disease.