Abstract
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 (“CD4+CD28− T cells” or “CD4+CD28null 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, CD4+CD28− 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 CD4+CD28− 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 CD4+CD28− phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association.
Highlights
CD28 is a costimulatory molecule expressed on naïve CD4+ and CD8+ T cells
CD4+CD28− T cells were first identified in the plaques of patients with unstable angina but since expansions of these cells have been reported in a range of cardiovascular (CV) conditions
In the context of inflammatory diseases such as rheumatoid arthritis (RA) and granulomatosis with polyangiitis (GPA), CMV-driven expansions of CD4+CD28− T cells are accentuated compared to otherwise healthy individuals, which will increase the potential for tissue damage [11, 32]
Summary
CD28 is a costimulatory molecule expressed on naïve CD4+ and CD8+ T cells. A permanent loss of CD28 occurs during antigen-driven differentiation toward a terminal phenotype. In the context of inflammatory diseases such as RA and GPA, CMV-driven expansions of CD4+CD28− T cells are accentuated compared to otherwise healthy individuals, which will increase the potential for tissue damage [11, 32]. The vast majority of studies investigating the presence and role of CD4+CD28− T cells in CVD and autoimmune diseases did so without considering participant CMV infection status, suggesting that many researchers are unaware of the association of an expansion of this subset with CMV infection.
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