Sara van den Berg

208 Chapter 8 antibody response to VSV [37]. In line with this, in humans it was shown that a lower percentage of class-switched B-cells pre-vaccination in CMV+ versus CMV- individuals, correlated with a reduced vaccine response to influenza [38]. It remains unclear how CMV leads to reduced B-cell class-switching [39]. Thus, no clear evidence on how CMV would impact the function of the immune system is present. COULD CMV BE BENEFICIAL FOR IMMUNE RESPONSES AGAINST HETEROLOGOUS INFECTIONS? Increasing evidence for a positive association between CMV and immune responses to heterologous infections Despite the many reported negative associations between CMV infection and the function of the immune system, there is currently increasing evidence for a positive association between CMV infection and immune responses to heterologous infections, especially in younger adults. A model in which CMV might be beneficial during young adulthood, and become detrimental over time during CMV infection has been proposed [40]. A positive association has been observed between CMV and the antibody response to influenza in humans in CMV+ mice within 3 months after CMV infection compared to CMV– mice [15]. This association was explained by IFN γ -dependent bystander activation, as increased IFN γ levels in human were associated with increased influenza antibody responses and IFN γ knock-out mice showed increased virus titers and decreased antibody responses [15]. In older adults, we found increased T-cell responses to influenza virus infection early after infection in CMV+ as compared to CMV- individuals, and a positive association between influenza virus-specific and CMV-specific T-cell responses was observed later on. However, this was not associated with levels of IFN γ in serum ( chapter 4 ). Positive associations were previously observed between CMV-specific T-cell responses and influenza virus T-cell responses [23], and SEB responses [26]. We observed similar associations between CMV-specific T-cell responses and SEB T-cells responses and T-cell responses after CD3/28 stimulation in CMV+ individuals ( chapter 7 , data not shown). Whether these associations are merely explained by inter-individual differences in size of T-cell responses, are due to cross-reactivity of T-cells, to bystander effects on other antigen-specific T-cells or non-antigen specific memory T-cells (virtual memory cells), remains unclear. Alternatively, NK cells might play a role, which have been shown to be affected by CMV as well [41], are not specific to a specific peptide, and might also respond in Elispot assays. The effect of publication bias and chance A beneficial effect of CMV on the immune system might be more likely than previously anticipated. We showed that a publication bias towards a negative association of CMV and the response rate to influenza antibody vaccination is present ( chapter 3 ). Currently, publications concluding a beneficial effect of CMV on immune response to a heterologous infection seem to increase in number. This indicates that the publications of a negative association between CMV infection and the immune response to influenza, might be merely variation around the possible truth: CMV does not affect the function of the immune system