Myelin and non-myelin immune responses in Multiple sclerosis

About This Grant

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). Susceptibility to MS is significantly associated with Class II alleles, in particular DRB1*15:01:01(DR15). Autoimmune response of the self-reactive CD4 T cells to myelin antigens is a major component of MS immunopathogenesis. Several CNS antigens are thought to be the targets for CD4 T cells and there are numerous viral and bacterial peptides that activate myelin basic protein (MBP)-specific T cells. This suggests that cross-reactivity of CD4 T cells might represent one mechanism whereby infections trigger disease. Myelin antigens are widely used to induce Experimental autoimmune encephalomyelitis (EAE). The actual myelin-reactive CD4 T cells potential cross- reactivity is very poorly characterized. To better define the T cell receptor (TCR) repertoire and its specificity in MS, we applied single cell paired TCR sequencing method, an algorithm to determine convergence of TCRs across individuals, and a robust platform for antigen discovery. Without enriching the T cells for any particular antigen specificity, we performed unbiased TCR sequencing of activated T cells from the blood and cerebrospinal fluid (CSF) of MS patients and healthy controls. In MS patients, we found higher clonal expansion and overlap of CD4 T cells in the blood and CSF, convergence of CD4 TCRs among multiple DR15 MS patients with common sequences/motifs, and cross-reactivity to human adenovirus (HAdV) peptide and with MBP. We generated DR15 tetramer with HAdV-peptide and in a small new cohort of DR15 patients and controls show the existence of HAdV and MBP cross-reactive CD4 T cells in the blood. Moreover, we generated a new HAdV-TCR transgenic mice to test hypothesis of cross-reactivity. Altogether, we show that a convergent CD4 TCR from multiple MS patients react with MBP and a peptide from viral origin and these cells can be detected in the blood of patients. Altogether, our results showed that CD4 T cells in MS cross-react to MBP and a peptide from viral origin. Therefore, our central hypothesis is that cross-reactive myelin specific CD4 TCR repertoire in a subpopulation of MS patients is triggered by adenovirus antigen. We will test this hypothesis with the following aims: Aim 1. To assess the cross-reactive CD4 TCR repertoire between MBP- and HAdV in MS patients and healthy individuals. Aim 2. To mechanistically determine the impact of a HAdV- and MBP-cross-reactive CD4-TCR in mouse model.