Daan Pieren

170 Chapter 6 Finally, we could extend these findings to COVID-19, as we had the unique opportunity at the start of the COVID-19 pandemic to assess KIR + RA + T cells in individuals infected with SARS-CoV-2, in whom KIR + RA + T cells became a highly activated cell subset during acute SARS-CoV-2 infection. Based on our efforts, we know how to characterize both KIR + RA + and NKG2A + RA + CD8 + T cells ( Figure 2B ) and we defined a new regulatory CD8 + T-cell subset that adds to the current classification of T-cell subsets and may contribute to aggravation of viral respiratory disease in older adults. Potential Suppressive Mechanisms of KIR + RA + T cells An important question that remains unanswered is by what mechanism KIR + RA + T cells suppress proliferation of other CD8 + T cells and thereby potentially impair anti-viral CD8 + T-cell responses. It is important to identify how KIR + RA + T cells exert suppression. This to eventually develop strategies to enhance protection and/or treat severe disease in older adults if KIR + RA + indeed suppress protective anti-viral responses. Here, we speculate on potential ways that KIR + RA + T cells exert immunosuppressive action based on the characteristic markers we found in chapter 5 . These hypotheses are also summarized in figure 3 . The co-inhibitory receptor TIGIT To co-inhibitory receptor TIGIT is primarily expressed by CD4 + Tregs [47] as well as by part of the CD8 + T-cell population [48,49] and competes with the co-stimulatory receptor CD266 for binding to the same two ligands CD155 and CD112 [50,51]. We found that KIR + RA + T cells highly express TIGIT, while expression of CD226 was low, which indicates that binding of KIR + RA + T cells to CD155 and/or CD112 is primarily through TIGIT. The result of interaction of TIGIT with its ligand depends on the cell type that expresses TIGIT. For effector CD4 + and CD8 + T cells TIGIT-ligand interactions results in cell intrinsic impaired proliferation and effector function [48,50,52], whereas for CD4 + Tregs this interaction promotes suppression of the immune response [43,47,48]. As KIR + RA + T cells are TIGIT + , suppressive mechanisms mediated by TIGIT in CD4 + Tregs may point towards potential mechanisms of KIR + RA + T cell-mediated suppression. TIGIT-mediated suppression by CD4 + Tregs is currently thought to be an indirect suppressive mechanism. First, binding of TIGIT to CD155 on dendritic cells resulted in an increase of IL-10 production and a decrease of IL-12 production by dendritic cells and conversion of the dendritic cell into a tolerogenic dendritic cell [51]. Second, interaction of TIGIT + CD4 + Tregs with effector CD4 + T cells indirectly suppressed effector-cell proliferation, as CD4 + Tregs secreted immunosuppressive IL-10 and fibrinogen-like protein 2 (Fgl2)