title: Stimulatory killer Ig-like receptors modulate T cell activation through DAP12-dependent and DAP12-independent mechanisms.
abstract: Stimulatory killer Ig-like receptors (KIRs) are expressed by various lymphocytes, including NK cells and subsets of T cells. In NK cells, KIRs associate with the adapter molecule KARAP/DAP12, which confers the ability to function as an independent activation unit. The function of KIRs and killer cell activating receptor-associated protein (KARAP)/DAP12 in T cells is unclear. By flow cytometry, we demonstrated that CD4+CD28null T cells heterogeneously express KIRs and/or KARAP/DAP12. In clones that lacked expression of KARAP/DAP12, the stimulatory KIR KIR2DS2 signaled through the JNK pathway, but did not activate the ERK pathway. However, in the presence of KARAP/DAP12, stimulation through KIR2DS2 led to phosphorylation of both JNK and ERK. Transfection experiments confirmed that KIR2DS2-mediated ERK phosphorylation was dependent on KARAP/DAP12. The differential signaling of KIR2DS2 through association with alternative adapter molecules resulted in differential regulation of cellular activity. In clones that lacked expression of KARAP/DAP12, stimulation of KIR2DS2 did not induce cytotoxicity. However, KIR2DS2 did augment suboptimal TCR stimulation, leading to enhanced IFN-gamma production. In clones that expressed KARAP/DAP12, KIR2DS2 directly activated both cytotoxicity and IFN-gamma production without the need for TCR-derived signals. The function of stimulatory KIRs in T cells is determined by the expression of the appropriate adapter molecule. Expression of KARAP/DAP12 is sufficient to convert a costimulatory KIR into a stimulatory molecule. These differing functions mediated by alternative signaling pathways have implications for the pathogenesis of diseases such as rheumatoid arthritis and acute coronary syndromes, in which aberrant expression of KIRs on T cells is frequently observed.
authors.affiliation: Departments of Medicine and Immunology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Snyder
authors.forename: Takako
authors.initials: T
authors.lastname: Nakajima
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leibson
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002461:Cell Line, Transformed; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000502:physiology*; D054340:Receptors, KIR; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C433932:KIR2DS2 protein, human; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D054340:Receptors, KIR; C110546:TYROBP protein, human; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases