title: De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes.
abstract: The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4+ T cells with a unique phenotype, CD4+CD28null, are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4+CD28+ T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4+CD28null T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4+CD28null T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4+CD28null T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs (P<0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4+ T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4+CD28null T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4+CD28null T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.
authors.affiliation: Departments of Medicine, Mayo Clinic, Rochester, Minn 55905, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Nakajima
authors.forename: Omer
authors.initials: O
authors.lastname: Goek
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Zhang
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Kopecky
authors.forename: Robert L
authors.initials: RL
authors.lastname: Frye
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D018106:CD28 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D002999:Clone Cells; D003327:Coronary Disease / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D005810:Multigene Family; D020033:Protein Isoforms / Q000096:biosynthesis; D011506:Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000378:metabolism; D054340:Receptors, KIR; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C433932:KIR2DS2 protein, human; D008565:Membrane Proteins; D020033:Protein Isoforms; D011506:Proteins; D011971:Receptors, Immunologic; D054340:Receptors, KIR; C110546:TYROBP protein, human