Sara van den Berg

212 Chapter 8 Our study suggests that the maintenance of high numbers of CMV-specific CD8 + T-cells does not require a substantially altered production or death rate compared to other memory CD8 + T-cells. Thus, this would suggest that maintenance of CMV-specific T-cells numbers is accomplished by similar dynamics than other antigen-specific T-cells of lower numbers. Thus, our work entails three new insights, namely (1) the effect of duration of CMV infection on the magnitude of the CMV-specific T-cells response is limited, (2) older age, regardless of duration of CMV infection, is associated with increased CMV-specific T-cell CD4 + responses, and (3) CMV-specific T-cells have similar underlying dynamics as bulk memory. These insights argue against both an increase of CMV-specific T-cell numbers over time as well as an effect of viral reactivation on the CMV-specific T-cell dynamics. If we incorporate these three findings in the model of memory inflation, no large role for viral reactivation and TCR triggering in the maintenance of high CMV-specific T-cell numbers is to be expected ( Figure 1, model B ). Alternative model and further research Our results challenge the mainstream of ‘T-cell memory inflation by viral reactivation’ and highlight that the underlying mechanism of the large CMV-specific T-cell responses in humans needs further attention. Further research into the association between age at the moment of CMV-seroconversion and both CD4 + and CD8 + CMV-specific T-cell responses shortly after seroconversion ask for further attention, starting with mouse studies. To further understand the phenomenon of memory inflation, two other questions would be particularly of interest in further research. The first question is if memory inflation of CMV-specific T-cells occurs in the first years after primary CMV infection. Obviously, in humans the moment of primary CMV infection is typically unknown, making it very complicated to draw firm conclusions on memory inflation, as this might already have occurred short-term after CMV-seroconversion. In fact, the initial contraction phase after the T-cell peak during primary infection or the set point within 1 or 2 years after primary infection might play a more crucial role in the establishment of these large T-cell numbers. To address this, others have investigated the CMV-specific T-cell response in recipients of a kidney transplant when a CMV+ donor kidney was transplanted into a CMV- recipient. These studies also revealed no direct evidence for memory inflation [48-50], although the percentage effector memory of total CMV-specific T-cells did seem to increase over time [48]. However, these patients were undergoing various degrees of immunosuppression. Further research, although very challenging, would of course ideally be performed in recently CMV-seroconverted healthy individuals to investigate the T-cell response in the first years after primary CMV infection. It might be that, maybe especially when primary CMV infection occurs in older adults affected by an aged immune system, memory inflation of CMV-specific T-cells will occur ( Figure 1, Model C ).