Latent Cytomegalovirus Infection in Rheumatoid Arthritis and Increased Frequencies of Cytolytic LIR‐1+CD8+ T Cells

OBJECTIVE Leukocyte immunoglobulin-like receptor 1 (LIR-1) is up-regulated by cytomegalovirus (CMV), which in turn, has been associated with premature aging and more severe joint disease in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the expression and functional significance of LIR-1 in CMV-positive RA patients. METHODS We determined the phenotype, cytolytic potential, CMV-specific proliferation, and HLA-G-triggered, LIR-1-mediated inhibition of interferon-γ secretion of LIR-1+ T cells in RA patients and healthy controls. RESULTS We found increased frequencies of CD8+ T cells with CMV pp65-specific T cell receptors in CMV-positive RA patients as compared to CMV-positive healthy controls. CMV-specific CD8+ T cells in these patients were preferentially LIR-1+ and exhibited a terminally differentiated polyfunctional phenotype. The numbers of LIR-1+CD8+ T cells increased with age and disease activity, and showed high levels of reactivity to CMV antigens. Ligation of LIR-1 with soluble HLA-G molecules in vitro confirmed an inhibitory role of the molecule when expressed on CD8+ T cells in RA patients. CONCLUSION We propose that latent CMV infection in the context of a chronic autoimmune response induces the recently described "chronic infection phenotype" in CD8+ T cells, which retains anti-infectious effector features while exhibiting autoreactive cytolytic potential. This response is likely dampened by LIR-1 to avoid overwhelming immunopathologic changes in the setting of the autoimmune disease RA. The known deficiency of soluble HLA-G in RA and the observed association of LIR-1 expression with disease activity suggest, however, that LIR-1+ T cells are insufficiently controlled in RA and are still likely to be involved in the pathogenesis of the disease.