Chronic stimulation of T cells leads to a loss of the co-stimulatory molecule CD28. The expansion of so-called "CD4+CD28null T cells is associated with various autoimmune and chronic inflammatory disorders such as rheumatoid arthritis, Graves' disease and Wegener's granulomatosis. Increased frequency of CD4+CD28null T cells was also demonstrated in a subgroup of MS patients. Our research group reported that these cells are partially autoreactive, possess cytotoxic properties and accumulate in active MS lesions. It is, however, unclear which genetic and immunological factors lead to the expansion of CD4+CD28null T cells with MS and whether these cells actually contribute towards the pathological process in the brain. In this project we are attempting to identify these factors. The results of this study may form the basis for the development of selective therapies for MS.