Poster abstracts

Poster number 98 submitted by Priscilla Lee

Identifying critical signals from antigen-presenting cells for generating a pathogenic T cells in multiple sclerosis

Priscilla Lee (Molecular Cellular and Developmental Biology Graduate Program), Yuhong Yang (Department of Neurology), Michael Racke (Department of Neurology), Amy Lovett-Racke (Department of Microbial Infection and Immunity)

Abstract:
While it is generally accepted that Multiple Sclerosis (MS) is a T cell-mediated disease, the factors determining the encephalitogenicity of T cells remains unclear. Myelin-specific T cells generated with antigen presenting cells (APCs) plus myelin peptide are encephalitogenic, whereas T cells generated with anti-CD3/CD28 antibodies are not, suggessting that APCs provide critical signals beyond T cell receptor activation and co-stimulation, contributing to an encephalitogenic phenotype. To recapitulate the signals provided by APCs, naïve myelin-specific CD4+ T cells were activated with anti-CD3/CD28 in the presence of various cytokines. The degree of encephalitogenicity of T cells was examined by the severity of experimental autoimmune encephalomyelitis (EAE). Although no single cytokine was sufficient, the combination of IL-6/IL-23 or IL-12/IL-23 generated highly encephalitogenic T cells. IL-6 and IL-12 induced the initial expression of IL-23R on naïve T cells, and IL-23 further enhanced the expression of its own receptor and the encephalitogenicity. Neutralizing IL-6 or IL-12 with antibodies significantly reduced the severity of EAE, which was induced by APC-generated T cells. Furthermore, IL-23 signling activated not only STAT3, an established pathway under IL-23R, but also STAT4, which was thought to be restricted to Th1 cells. Loss of STAT4 in T cells generated with IL-6/IL-23 ameliorated the severity of EAE, indicating STAT4 is essential for IL-23-induced encephalitogenicity. We have identified that IL-6/IL-23 or IL-12/IL-23 combination in addition to TCR activation and co-stimulation were the miminal signals necessary to generate encephalitogenic T cells. This provides potential targets that can be manipulated therapeutically, resulting in innovative treatments for MS.

Keywords: T cell , multiple sclerosis, autoimmunity