Abstract
While CD8+ T cells specific for human cytomegalovirus (HCMV) have been extensively studied in both healthy HCMV seropositive carriers and patients undergoing immunosuppression, studies on the CD4+ T cell response to HCMV had lagged behind. However, over the last few years there has been a significant advance in our understanding of the importance and contribution that CMV-specific CD4+ T cells make, not only to anti-viral immunity but also in the potential maintenance of latently infected cells. During primary infection with HCMV in adults, CD4+ T cells are important for the resolution of symptomatic disease, while persistent shedding of HCMV into urine and saliva is associated with a lack of HCMV specific CD4+ T cell response in young children. In immunosuppressed solid organ transplant recipients, a delayed appearance of HCMV-specific CD4+ T cells is associated with prolonged viremia and more severe clinical disease, while in haematopoietic stem cell transplant recipients, it has been suggested that HCMV-specific CD4+ T cells are required for HCMV-specific CD8+ T cells to exert their anti-viral effects. In addition, adoptive T-cell immunotherapy in transplant patients has shown that the presence of HCMV-specific CD4+ T cells is required for the maintenance of HCMV-specific CD8+ T cells. HCMV is a paradigm for immune evasion. The presence of viral genes that down-regulate MHC class II molecules and the expression of viral IL-10 both limit antigen presentation to CD4+ T cells, underlining the important role that this T cell subset has in antiviral immunity. This review will discuss the antigen specificity, effector function, phenotype and direct anti-viral properties of HCMV specific CD4+ T cells, as well as reviewing our understanding of the importance of this T cell subset in primary infection and long-term carriage in healthy individuals. In addition, their role and importance in congenital HCMV infection and during immunosuppression in both solid organ and haemopoietic stem cell transplantation is considered.
Highlights
Over the last few decades research in both humans and murine models has clearly demonstrated that both the innate and adaptive branches of the immune response play a role in resolving both primary, reactivating and super-infections with cytomegalovirus (CMV)
It is clear that there is increasing evidence to show that CD4+ T cells play a significant role in anti-viral immunity to human cytomegalovirus (HCMV)
There is development of a CMV-specific CD4+ T cell population that persists in the T cell repertoire of healthy adults, suggesting that this population of T cells is required for a healthy immune response to control periodic episodes of viral reactivation over a life time of the infected host
Summary
Over the last few decades research in both humans and murine models has clearly demonstrated that both the innate and adaptive branches of the immune response play a role in resolving both primary, reactivating and super-infections with cytomegalovirus (CMV). Another study involving 29 liver transplant patients found that CD4+ T cells producing IFN-γ, IL-2 or both cytokines in response to a peptide mix containing pp65, IE1, and CMV lysate occurred at a lower frequency in recipients who subsequently develop viremia (Nebbia et al, 2008).
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