Functional Analysis of Killer Ig-Like Receptor-Expressing Cytomegalovirus-Specific CD8+ T Cells

Abstract

Killer Ig-like receptors (KIR) are expressed by human NK cells and T cells. Although Ag-specific cytolytic activity and cytokine production of KIR+ T cells can be inhibited by KIR ligation, the effect of KIR on proliferation is unclear. KIR+ T cells have been reported to have a general proliferative defect. To investigate whether KIR+ T cells represent end-stage dysfunctional T cells, we characterized KIR+ CMV-specific T cells in allogeneic stem cell transplantation patients and healthy donors. In both patients and healthy donors, a significant percentage KIR+ T cells was detected at various time points. All stem cell transplantation patients studied showed KIR expression on CMV-specific T cells, while not all donors had KIR-expressing CMV-specific T cells. From two of the patients and one donor KIR+ CMV-specific T clones were isolated and analyzed functionally. T cells were detected that expressed KIR that could not encounter their corresponding KIR ligands in vivo, illustrating that KIR expression by these T cells was not based on functional selection but a random process. Our data demonstrate that KIR+ T cells are fully functional T cells that are only restricted in effector functions and proliferation upon KIR ligation. The level of KIR-mediated inhibition of the effector functions and proliferation depended on the strength of TCR stimulation. We observed no diminished general proliferative capacity and therefore we conclude that these T cells do not represent end-stage dysfunctional T cells.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…KIR expression is weak or absent in immature NKG2A + CD56 bright NK cells and increases gradually with maturation, reaching its maximum level in NKG2A −  CD56 dim NK cells 148, 149, 150. Similar observation was made for T cells, in which KIR expression is virtually absent in CD4 and CD8 naive T cells and reaches its maximal level in differentiated effector memory T cells 2, 5, 151, 152. Accordingly, KIR expression is low in less mature cord blood NK and T cells compared with healthy adult control cells 153, 154…”

“…Although NK cell KIR repertoire is considered stable in time, the frequency of KIR + T cells increases with age, due to accumulation of terminally differentiated T cells 141. Interestingly, HCMV‐specific CD8 T cells almost completely lack KIR expression, and the specificity of KIR‐expressing cells remains largely unknown 2, 5, 7, 151, 179. In contrast, it was shown that KIR +  CD4 + T cells display specificity against HCMV but not Epstein–Barr virus or HSV‐1 4.…”

Contribution of functional KIR3DL1 to ankylosing spondylitis

“…KIR-MHC class I interaction can inhibit cytolytic activity and cytokine production in T cells, but the level of KIR-mediated inhibition of T-cell effector functions depends on the strength of T-cell antigen receptor stimulation. [20][21][22] Therefore, consistent with the role of KIRs on NK cells, KIRs probably regulate the activation and inhibition of specific T-cell subpopulation(s).…”

CD8 T cells express randomly selected KIRs with distinct specificities compared with NK cells

“…22,25,[34][35][36] In NK cells, the strength of the inhibitory interaction between KIRs and their cognate HLA class I molecules tunes the functional responsiveness of the cell during their development in an education process termed licensing. 18 However, in mice, intraepithelial T cells were not educated by interactions with self-MHC class I molecules, suggesting that such education is an NK cell-specific process.…”

“…[19][20][21][22][23][24] With respect to CD8 T cells, KIR expression starts to appear on effector memory CD8 cells, and a substantial fraction of terminally differentiated effector CD8 T cells are KIR ϩ . 20,22,25 The function of KIRs on CD8 T cells has been studied to some extent. Although most studies have been performed with KIR ϩ CD8 T-cell clones, it is clear that inhibitory KIRs can modulate T-cell receptor (TCR) signaling and dampen CD8 T-cell responses, whereas activating KIRs can enhance functional T-cell responses.…”