title: Multiplex and genome-wide analyses reveal distinctive properties of KIR+ and CD56+ T cells in human blood.
abstract: 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 real-time but not KIR(+)CD56(-) 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.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Wing Keung
authors.initials: WK
authors.lastname: Chan
authors.forename: Piya
authors.initials: P
authors.lastname: Rujkijyanont
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Rafijul
authors.initials: R
authors.lastname: Bari
authors.forename: Neha
authors.initials: N
authors.lastname: Das Gupta
authors.forename: Martha
authors.initials: M
authors.lastname: Holladay
authors.forename: Barbara
authors.initials: B
authors.lastname: Rooney
authors.forename: Wing
authors.initials: W
authors.lastname: Leung
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D058070:Asymptomatic Diseases; D016026:Bone Marrow Transplantation; D019002:CD56 Antigen / Q000032:analysis; D018959:CD57 Antigens / Q000032:analysis; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D055106:Genome-Wide Association Study; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology*; D055442:Metabolome; D060885:Multiplex Polymerase Chain Reaction; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000032:analysis; D055611:Natural Killer T-Cells / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D054340:Receptors, KIR / Q000032:analysis; D054343:Receptors, KIR2DL2 / Q000032:analysis; D054344:Receptors, KIR2DL3 / Q000032:analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016615:Telomere / Q000648:ultrastructure; D058504:Th17 Cells / Q000276:immunology; D014019:Tissue Donors; D059467:Transcriptome; D014775:Virus Activation; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D019002:CD56 Antigen; D018959:CD57 Antigens; C515077:KIR2DL2 protein, human; C515078:KIR2DL3 protein, human; C527059:KLRC2 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3