Clonal Vctl2.1 + T Cell Expansions in the Peripheral Blood of Rheumatoid Arthritis Patients

Rheumatoid arthritis (R.A) represents a heterogenous disease characterized by chronic polyarthritis. Most patients with adult RA inherit HLA-DR4 or -DR1 major histocompatibility complex (MHC) genes. While the molecular basis for this genetic predisposition is unknown, the major function of these MHC-encoded molecules is to present peptides to T lymphocytes. It is hypothesized that an endogenous or environmental antigen initiates a MHC-restricted immune response mediated by T lymphocytes, which is followed by a chronic inflammatory reaction involving many cell types. In chronic RA, previous or ongoing antigenic activation might result in detectable skewing of the peripheral ot/~ T cell receptor (TCR) repertoire. Here we demonstrate a marked expansion of Vc~12.1-bearing CD8 + T cells in the peripheral blood (mean, 22%; range, 10-43%) of >15% of RA patients. A major proportion of these patients shared HLA-DQ2 in addition to the expected high frequency DR1 and DR4 alleles. Detailed molecular analysis in three of the RA patients with elevated Vot12.1 + T cells identified repeated TCR. ol chain sequences consistent with clonal Vot12.1 + ,CD8 + T cell expansion. In addition to shared TCR Vo~12.1 germline gene usage among unrelated subjects, a conserved Jot motif was also detected. Together, these results suggest an antigen-driven mechanism ofT cell expansion in these patients and may offer a new approach in examining specific antigens that stimulate T cells in RA.