title: Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors.
abstract: Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a large clonal population of blood cells deriving from hematopoietic stem cells (HSCs) deficient in glycosylphosphatidylinositol (GPI)-anchored surface molecules. A current model postulates that PNH arises through negative selection against normal HSCs exerted by autoreactive T cells, whereas PNH HSCs escape damage. We have investigated the inhibitory receptor superfamily (IRS) system in 13 patients with PNH. We found a slight increase in the proportion of T cells expressing IRS. In contrast to what applies to healthy donors, the engagement of IRS molecules on T cells from patients with PNH elicited a powerful cytolytic activity in a redirected killing assay, indicating that these IRSs belong to the activating type. This was confirmed by clonal analysis: 50% of IRS+ T-cell clones in patients with PNH were of the activating type, while only 5% were of the activating type in healthy donors. Moreover, the ligation of IRS induces (1) production of tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) and (2) brisk cytolytic activity against cells bearing appropriate IRS counter-ligands. In addition, these IRS+ T cells show natural killer (NK)-like cytolytic activity to which GPI- cells were less sensitive than GPI+ cells. Thus, T cells with NK-like features, expressing the activating isoforms of IRS, may include effector cells involved in the pathogenesis of PNH.
authors.affiliation: Laboratory of Experimental Oncology, Department of Translational Oncology, National Institute for Cancer Research, Genoa, Italy. alessandro.poggi@istge.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Simone
authors.initials: S
authors.lastname: Negrini
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Zocchi
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Massaro
authors.forename: Lucia
authors.initials: L
authors.lastname: Garbarino
authors.forename: Sonia
authors.initials: S
authors.lastname: Lastraioli
authors.forename: Lucia
authors.initials: L
authors.lastname: Gargiulo
authors.forename: Lucio
authors.initials: L
authors.lastname: Luzzatto
authors.forename: Rosario
authors.initials: R
authors.lastname: Notaro
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000737:chemistry; D017252:CD3 Complex / Q000096:biosynthesis; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005838:Genotype; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000097:blood*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D017261:Glycosylphosphatidylinositols; D008024:Ligands; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma