Expansions of Cytotoxic CD4CD28 T Cells Drive Excess Cardiovascular Mortality in Rheumatoid Arthritis and Other Chronic Inflammatory Conditions and Are Triggered by CMV Infection.

A large proportion of cardiovascular (CV) pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4 T cells characterized by loss of CD28 ("CD4CD28 T cells" or "CD4CD28 cells") are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4CD28 T cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1-2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in CVD, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4CD28 T cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV infection. They are likely to be responsible for the excess CV mortality observed in these situations. The CD4CD28 phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association.