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

Abstract

ObjectiveLeukocyte 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.MethodsWe 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.ResultsWe 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.ConclusionWe 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.

Autoimmune arthritis induces paired immunoglobulin‐like receptor B expression on CD4+ T cells from SKG mice

“…Previously, we and others have described an association of latent CMV–triggered immunosenescence with RA, in particular in patients with more severe disease . LIR‐1, an inhibitory receptor associated with T‐cell compartment deviations characteristically induced in CMV infection, was found to be up‐regulated on CD8 + T cells from RA patients .This prompted us to investigate the expression of its murine ortholog PIR‐B in an animal model of RA. We report here for the first time that PIR‐B is up‐regulated on peripheral CD4 + T cells of SKG mice.…”

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

“…Rheumatoid arthritis Latent CMV infection influences the clinical course and outcome of rheumatoid arthritis (RA) (Davis et al 2012;Pierer et al 2012), and CMV has been associated with more severe joint disease in patients with RA (Rothe et al 2016). Specific immunopathogenic mechanisms through which CMV could contribute to aggravation of joint damage in RA patients include the expansion of CMV-specific CD4+ CD28− (Pawlik et al 2003) and CD8+CD28− (Rothe et al 2016) T cells, which directly contribute to tissue lesions.…”

“…Specific immunopathogenic mechanisms through which CMV could contribute to aggravation of joint damage in RA patients include the expansion of CMV-specific CD4+ CD28− (Pawlik et al 2003) and CD8+CD28− (Rothe et al 2016) T cells, which directly contribute to tissue lesions.…”

Cytomegalovirus infection alters phenotypes of different γδ T‐cell subsets in renal transplant recipients with long‐term stable graft function

“…LIR‐1 and CD57 are markers of terminal differentiation on αβ T‐cells . Median percentage of LIR‐1 + Vδ2 + γδ T‐cells was similar in CMV + DNA− RTR and controls (CMV+ and CMV−) but low in CMV− RTR (Table ).…”