Antigen Presentation by B Cells in T Cell Mediated Autoimmunity

Dana-Farber Cancer Inst, Boston MA

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Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model that reproduces many of the clinical and pathological features of multiple sclerosis (MS). While it is well documented that myelin specific T cells, Th1 and Th17 cells are important for the initiation of the disease, the role of B cells and antibodies in the disease process is not well understood. The development and the progression of EAE, like other autoimmune diseases, results from the pathogenicity of effector T cells and the negative regulation imposed by regulatory T cells (Tregs). However, the lack of a reliable marker for regulatory T cells has made it difficult to study the interplay between myelin specific effector T cells and regulatory T cells. To study the effect of antigen specific B cells in the generation of pathogenic T cells, we have established a mouse model (2D2xTH mice) in which both T and B cells are specific for the same myelin protein, myelin oligodendrocyte glycoprotein (MOG). The majority of 2D2xTH mice (about 59%) develop a very severe form of spontaneous EAE within 6 weeks of age that is similar to a sub-form of MS called Devic disease, characterized by the presence of inflammatory foci restricted to the spinal cord and optic nerve. By gene expression profiling, we have identified IL-22 as a cytokine differentially upregulated in the spinal cord of mice with Devic disease. We have also generated a Foxp3-EGFP knock-in mouse in order to track CD4+CD25+ Treg cells during the course of an ongoing immune response. With the help of l-Ab/MOG35-55 tetramer (developed in collaboration with Kai Wucherpfennig) we are able to track development and effector functions of MOG specific pathogenic and regulatory T cells. Based on our results, we propose that antigen presentation by MOG-specific B cells generates highly pathogenic T cells and limits the generation and function of MOG specific CD4+CD25+ regulatory T cells which results in the development of a very severe EAE. We will test whether: 1) MOG specific B cells participate in disease progression by the secretion of MOG specific pathogenic antibodies and /or by preferential antigen presentation to MOG-specific T cells;2) T cells generated in the presence of cognate antigen specific B cells are more encephalitogenic and produce more IL-17 and IL-22;3) MOG specific B cells limit the expansion and/or function of regulatory T cells responsible for keeping pathogenic T cells under check. The role of IL-22 in generating highly pathogenic T cells and development of Devic-like disease in mice will be evaluated by using IL-22 deficient mice. The proposed studies will allow us to better characterize the mechanism by which autoantigen specific B cells induce autopathogenic T cells and how they regulate the expansion and function of antigen specific regulatory T cells. Furthermore, our proposed studies will allow us to study how antigen specific B cells might control the development of an organ specific T cell mediated autoimmune disease.