Multiple sclerosis (MS) is a prototypic CD4+ T cell-mediated autoimmune disease that damages the central nervous system. MS affects young adults and women twice as often as men. Neurological deficits cause substantial disability at an early age with high socioeconomic impact.Both a complex genetic trait and environmental factors are involved in MS etiology. Similar to other autoimmune diseases it has been known for almost 40 years that certain HLA-class II genes, in MS the two DR15 alleles DRB1*15:01 and DRB5*01:01, confer by far most of the genetic risk. Despite this clear role remarkably little is known about the functional contribution of these genes to MS pathogenesis, and this holds also true for all other T cell-mediated autoimmune diseases. It is assumed that the DR15 alleles present peptides from organ-specific self-proteins to T cells and select an autoreactive CD4+ T cell repertoire that can be activated by certain environmental triggers. Interestingly, the effects of the three known environmental risk factors in MS, Epstein Barr virus (EBV), low vitamin D3 and smoking, are all amplified by DR15.This core issue of research on autoimmune diseases and also MS, how disease-associated HLA-class II molecules contribute to disease development at the functional level, will be studied with state-of-the-art methodologies and a series of novel approaches. These will include in silico modeling approaches, studies of self-peptides, T cell receptor (TCR) repertoire and HLA-DR/peptide complexes, clonally expanded T cells from MS brain tissue and hypothesis-open methods such as combinatorial chemistry and tissue-derived cDNA libraries to identify target antigens. Finally, translational studies will investigate the relationship between the above aspects and MS disease heterogeneity and explore antigen-specific tolerization in proof-of concept clinical trials in MS.