A Novel Cytomegalovirus-Induced Regulatory-Type T-Cell Subset Increases in Size During Older Life and Links Virus-Specific Immunity to Vascular Pathology

Background. Cytomegalovirus (CMV) infection directly targets vascular endothelium and smooth muscle and at older ages is associated with accelerated vascular pathology and mortality. CMV-specific cellular immunity might directly contribute to this process. Methods. Conventional ex vivo activation-induced T-cell responses to 19 dominant CMV antigens, along with CMV-specific inducible regulatory-type CD4(+) T cells (iTregs), were measured in healthy older people, using a novel protocol that included classic Treg markers alongside the activation marker CD134. Measurements were correlated with diastolic, systolic, and mean arterial blood pressure, a surrogate marker for arterial stiffness. Results. CMV-specific iTregs recognized the same antigens as conventional CD4(+) T cells and were significantly more frequent at older ages. They suppressed antigen-specific and nonspecific proliferation and in large part expressed Foxp3. Frequencies of CMV-specific iTregs and CD8(+) T cells (summated response) were significantly associated with diastolic and mean arterial pressures. Confounders, including age, body mass index, smoking, antihypertensive medication use, or C-reactive protein levels, did not explain these observations. Conclusions. A novel CMV-induced regulatory-type CD4(+) T-cell subset is readily detectable in CMV-infected people and, like the aggregate CD8(+) T-cell response to the most dominant CMV antigens, is quantitatively associated with arterial stiffness in older life. Whereas CD8(+) effector T cells might directly cause vascular injury, iTregs may attenuate this response.