Daan Pieren

176 Chapter 6 KIR + RA + T cells in Infectious Disease: a Double-Edged Sword In chapter 5 we show that KIR + RA + T cells can exert suppression and that the presence of activated KIR + RA + T cells in peripheral blood positively correlates with the total duration of symptoms in influenza A virus-infected older adults. We therefore speculate that suppression of anti-viral CD8 + T cells by KIR + RA + T cells may lead to prolonged illness, thereby concluding that the presence of activated KIR + RA + T cells during infection is unfavorable. This hypothesis is fueled by studies showing that CD4 + Tregs are capable of suppressing protective CD8 + T cell responses in influenza A-infected mice [79], and genetically disrupting CD8 + Tregs enhances the T-cell response against acute viral infection [80]. However, it may still be that presence of highly activated KIR + RA + T cells prevented the occurrence of even longer duration of symptoms: what would have happened if these KIR + RA + T cells were not present? Hypothetically, absence of highly activated KIR + RA + T cells as regulatory cells may as well have resulted in uncontrolled killing by effector CD8 + T cells that fight virus-infected lung cells, potentially resulting in lung pathology and more severe disease. Arguing for this alternative hypothesis is a recent study showing that the co-inhibitory marker TIGIT limits pathological tissue damage after viral infection in mice [81]. This suggests that presence of TIGIT Hi KIR + RA + T cells may prevent excessive lung damage. Lastly, it remains to be established whether KIR + RA + T cells only suppress other activated effector T cells, or whether they can kill virally infected cells themselves as well. Recent evidence from research on HIV suggests that the human virtual memory cell subset may limit the viral reservoir by eliminating HIV-infected CD4 + T cells [82], indicating that KIR + RA + T cells may be a highly important cell subset in maintaining balance within the immune system by killing of infected cells as well as suppressing other T cells. Thus, future studies in humans and in vivo studies in mice should address whether the presence or absence of KIR + RA + T cells in the lung is favorable or unfavorable during viral infection and whether there is a tipping point between the number of KIR + RA + T cells being activated determining health or disease. KIR + RA + T cells: Bystander or Antigen-Specific T cells? Whether KIR + RA + T cells are bystander cells during viral infection or are activated due to recognition of viral antigens remains to be elucidated. Three arguments can be put forward why it is likely that KIR + RA + T cells are bystander cells during viral infection. First, we found that a large proportion of KIR + RA + T cells are activated as a consequence of influenza A virus infection (26% on average), as well as during infection with other respiratory viruses (averages ranging from 6% to 23%). These proportions are more than expected for an