Multiplex and genome-wide analyses reveal distinctive properties of KIR⁺ and CD56⁺ T cells in human blood

Killer cell Ig-like receptors (KIRs) on NK cells have been linked to a wide spectrum of health conditions such as chronic infections, autoimmune diseases, pregnancy complications, cancers, and transplant failures. A small subset of effector memory T cells also expresses KIRs. In this study, we use modern analytic tools including genome-wide and multiplex molecular, phenotypic, and functional assays to characterize the KIR+ T cells in human blood. We find that KIR⁺ T cells primarily reside in the CD56⁺ T population that is distinctively DNAM-1^high with a genome-wide quiescent transcriptome, short telomere, and limited TCR excision circles. During CMV reactivation in bone marrow transplant recipients, KIR⁺CD56 ⁺ T cells rapidly expanded in realtime but not KIR⁺CD562 T cells or KIR⁺ NK cells. In CMV⁺ asymptomatic donors, as much as 50% of CD56⁺ T cells are KIR⁺, and most are distinguishably KIR2DL2/3⁺NKG2C⁺CD57⁺. Functionally, the KIR⁺CD56⁺ T cell subset lyses cancer cells and CMVpp65-pulsed target cells in a dual KIR-dependent and TCR-dependent manner. Analysis of metabolic transcriptome confirms the immunological memory status of KIR⁺CD56⁺ T cells in contrast to KIR ^-CD56⁺ T cells that are more active in energy metabolism and effector differentiation. KIR-CD56⁺ T cells have >25-fold higher level of expression of RORC than the KIR⁺ counterpart and are a previously unknown producer of IL-13 rather than IL-17 in multiplex cytokine arrays. Our data provide fundamental insights into KIR⁺ T cells biologically and clinically.