Human cytomegalovirus (HCMV) infection and periodic re-activation is generally well controlled by the HCMV-specific T cell response in healthy people. While the CD8+ T cell response to HCMV has been extensively studied, the HCMV-specific CD4+ T cell effector response is not as well understood, especially in the context of direct interactions with HCMV infected cells. We screened the IFNγ and IL-10 response to 6 HCMV peptide pools (selected as the most frequently responded to in our previous studies: pp65, pp71, IE1, IE2, gB and US3) in 84 donors, aged 23 - 74 years. Predominantly the HCMV specific CD4+ T cell response to pp65, IE1, IE2 and gB was Th1 biased with neither loss nor accumulation of these responses with increasing age. A larger proportion of donors produced an IL-10 response to pp71 and US3 but the IFNγ response was still dominant. CD4+ T cells specific to the HCMV proteins studied were predominantly effector memory cells and produced both cytotoxic (CD107a expression) and cytokine (MIP1β secretion) effector responses. Importantly, when we measured the CD4+ T cell response to CMV infected Dendritic Cells in vitro, we observed that the CD4+ T cells produced a range of cytotoxic and secretory effector functions, despite the presence of CMV encoded immune evasion molecules. CD4+ T cell responses to HCMV infected dendritic cells were sufficient to control the dissemination of virus in an in vitro assay. Together the results show that HCMV-specific CD4+ T cell responses are highly functional even from elderly individuals and are directly anti-viral.

IMPORTANCE: Human cytomegalovirus (HCMV) infection is carried for a lifetime and in healthy people is kept under control by the immune system. HCMV has evolved many mechanisms to evade the immune response, possibly explaining why the virus is never eliminated during the hosts' lifetime. Dysfunction of immune cells associated with long-term carriage of HCMV has been linked with poor responses to new pathogens and vaccines when older. In this study we have investigated the response of a subset of immune cells (CD4+ T cell) to HCMV proteins in healthy donors of all ages demonstrating that the functionality of the CD4+ T cells is maintained. We have also shown that CD4+ T cells produce effector functions in response to HCMV infected cells and can prevent virus spread. Our work demonstrates that these HCMV-specific immune cells retain many important functions and help to prevent deleterious HCMV disease in healthy older people.