Rheumatoid arthritis (RA) is a heterogenous disease characterized by chronic polyarthritis in genetically predisposed individuals. A number of lines of evidence suggest that T cells may play an important role in RA. Our preliminary data reveal that 20% of RA patients have markedly expanded V-alpha12 bearing CD8+ T cells in their peripheral blood. These T cells have undergone clonal expansion based on the analysis of their V-alpha and V-beta sequences and have a conserved J-alpha motif in their junctional region. These cells carry the previously activated (CD45RO) phenotype and express markers of ongoing or chronic activation (MHC class II+ and VLA- 1+). The patients with expanded V-alpha12+ T cell populations have an increased frequency of the HLA-DQ2 allele. These features of the sequence analysis, including use of a single V-alpha (V-alpha12) and the presence of a J-alpha motif are consistent with an antigen driven expansion. The HLA-DQ2 association raises the possibility that this MHC molecule is involved in antigen presentation to the expanded T cells. We propose to study the specificity and function of these V-alpha12+/GD8+ T cells in order to understand their role in RA. The functions of the cells will be examined by cytokine analyses, and in vitro functional assays for help or inhibition of B and T cell responses. Their abundance in RCA peripheral blood (an average of 29-30% of all CD8+ T cells) suggests the potential for important functional effects in vivo either as regulatory or cytotoxic T cells. It is hypothesized that these may be autoreactive T cells that are restricted to DQ2 molecules or reactive to DQ2 peptides. The MHC restriction and peptide specificity of the V- alpha12+/CD8+ T cells will be characterized. These T cell clones and receptors provide a novel tool to examine the antigens and functions that may be of importance in this autoimmune disease.
