title: Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity.
abstract: Natural killer (NK) cells are innate lymphocytes that play an important role against viral infections and cancer. This effect is achieved through a complex mosaic of inhibitory and activating receptors expressed by NK cells that ultimately determine the magnitude of the NK-cell response. The T-cell immunoglobulin- and mucin domain-containing (Tim)-3 receptor was initially identified as a T-helper 1-specific type I membrane protein involved in regulating T-cell responses. Human NK cells transcribe the highest amounts of Tim-3 among lymphocytes. Tim-3 protein is expressed on essentially all mature CD56(dim)CD16(+) NK cells and is expressed heterogeneously in the immature CD56(bright)CD16(-) NK-cell subset in blood from healthy adults and in cord blood. Tim-3 expression was induced on CD56(bright)CD16(-) NK cells after stimulation with IL-15 or IL-12 and IL-18 in vitro, suggesting that Tim-3 is a maturation marker on NK cells. Whereas Tim-3 has been used to identify dysfunctional T cells, NK cells expressing high amounts of Tim-3 are fully responsive with respect to cytokine production and cytotoxicity. However, when Tim-3 was cross-linked with antibodies it suppressed NK cell-mediated cytotoxicity. These findings suggest that NK-cell responses may be negatively regulated when NK cells encounter target cells expressing cognate ligands of Tim-3.
authors.affiliation: Hawaii Center for AIDS, Department of Tropical Medicine, University of Hawaii, John A. Burns School of Medicine, Honolulu, 96813, USA. lndhlovu@hawaii.edu
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
authors.forename: Sandra
authors.initials: S
authors.lastname: Lopez-Vergès
authors.forename: Jason D
authors.initials: JD
authors.lastname: Barbour
authors.forename: R Brad
authors.initials: RB
authors.lastname: Jones
authors.forename: Aashish R
authors.initials: AR
authors.lastname: Jha
authors.forename: Brian R
authors.initials: BR
authors.lastname: Long
authors.forename: Eric C
authors.initials: EC
authors.lastname: Schoeffler
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fujita
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008024:Ligands; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015415:Biomarkers; D019002:CD56 Antigen; D003432:Cross-Linking Reagents; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008024:Ligands; D008565:Membrane Proteins; C522918:NCAM1 protein, human; D017452:Receptors, IgG