Molecular characterization of HCMV-specific immune responses: Parallels between CD8+ T cells, CD4+ T cells, and NK cells

Abstract

CD8+ T cells are important for immunity against human cytomegalovirus (HCMV). The HCMV-specific CD8+ T-cell response is characterized by the accumulation of terminally differentiated effector cells that have downregulated the costimulatory molecules CD27 and CD28. These HCMV-specific CD8+ T cells maintain high levels of cytotoxic molecules such as granzyme B and rapidly produce the inflammatory cytokine IFN-γ upon activation. Remarkably, HCMV-specific CD8+ T cells are able to persist long term as fully functional effector cells, suggesting a unique differentiation pathway that is distinct from the formation of memory CD8+ T cells after infection with acute viruses. In this review, we aim to highlight the most recent developments in HCMV-specific CD8+ T-cell differentiation, maintenance, tissue distribution, metabolism and function. HCMV also induces the differentiation of effector CD4+ T cells and NK cells, which share characteristics with HCMV-specific CD8+ T cells. We propose that the overlap in differentiation of NK cells, CD4+ and CD8+ T cells after HCMV infection may be regulated by a shared transcriptional machinery. A better understanding of the molecular framework of HCMV-specific CD8+ T-cell responses may benefit vaccine design, as these cells uniquely combine the capacity to rapidly respond to infection with long-term survival.