Latent CMV Infection Induces Chronic Infection Phenotype in RA

Results from a recent study suggest that a latent cytomegalovirus (CMV) infection in the setting of a chronic autoimmune responsive state induces a “chronic infection phenotype” in CD8+ T cells that exhibits autoreactive cytolytic potential. The findings of the study were published in Arthritis and Rheumatology.

The presence of latent CMV infection influences the clinical course of rheumatoid arthritis (RA), which is a T-cell-mediated autoimmune disease.  CMV infection has been reported to cause T-cell clonal expansions, creating a population of CMV antigen-reactive T cells.

Latent CMV infection is associated with increased expression of natural killer cell receptor leukocyte immunoglobulin-like receptor 1 (LIR-1) on the surface of CMV-reactive CD8+ T cells.  In healthy individuals, LIR-1 expression may limit damage resulting from a sustained anti-CMV immune response, suggesting that abnormal LIR-1 expression may be involved in RA in the setting of CMV infection.

To investigate the expression and function of LIR-1 in CMV-positive RA patients, researchers compared the phenotype, cytolytic potential, CMV-specific proliferation, and interferon-ƴ secretion of LIR-1+ T cells in RA patients against those in a healthy control group.

Researchers observed increased frequencies of CD8+ T cells with CMV pp65-specific T-cell receptors in CMV-positive RA patients. In these patients, CMV-specific CD8+ T cells were usually LIR-1+ and showed a terminally differentiated polyfunctional phenotype.

The number of LIR-1+ CD8+ T cells increased with age and disease activity, and the cells also showed high levels of reactivity to CMV antigens. The researchers also performed ligation of LIR-1 with soluble HLA-G molecules in vitro. They observed that the molecules had an inhibitory role when expressed on CD8+ T cells in RA patients.

“Our data suggest that the intricate network and finely tuned crosstalk of UL18, HLA-G, and classic [major histocompatibility complex] class I molecules with LIR-1 is distributed during the course of a CMV infection in RA,” the authors wrote. “As a consequence, deficiency of soluble HLA-G might diminish the inhibitory effects of LIR-1 on CD8+ T cells in CMV-positive RA patients.”

The authors concluded that the induced chronic infection phenotype is likely decreased by LIR-1 to avoid overwhelming immunopathologic changes in the setting of RA. The deficiency of HLA-G in RA and the association of LIR-1 expression with disease activity suggest that LIR-1+ T cells are poorly controlled in RA and may be involved in the pathogenesis of the disease.

They also note that LIR-1+ CD8+ T cells “might still be involved in the immunologic control of the latent CMV infection, which illustrates possible unwanted side effects of immunosuppression in this disease.”

Summary and Clinical Applicability

In comparison to healthy controls, LIR-1 is upregulated on T cells in RA patients, resulting in poor control of latent CMV infection. Furthermore, these LIR-1+ T cells in RA patients are polyfunctional and exhibit cytolytic potential.  

Thus, in RA, the increased expression of LIR-1 could result from an insufficiently controlled latent CMV infection, leading to higher numbers of T cells that retain effector features, including cytolysis. LIR-1+ T cells may be insufficiently controlled in RA and are likely involved in RA pathogenesis.

This suggests that cells with abnormalities in LIR-1 expression may play an important role in RA pathogenesis and may also represent a future pharmaceutical target.

Reference

Rothe K, Quandt D, Schubert K, et al. Latent cytomegalovirus infection in rheumatoid arthritis and increased frequencies of cytolytic LIR-1+ CD8+ T cells. Arthritis Rheumatol. 2016;68(2):337-346. doi: 10.1002/art.39331.