title: p40 molecule regulates NK cell activation mediated by NK receptors for HLA class I antigens and TCR-mediated triggering of T lymphocytes.
abstract: p40 was previously described as a regulatory molecule capable of inhibiting both the natural and the CD16-mediated cytotoxicity of NK cells. In this study, we analyze the effect of p40 molecule engagement on the NK cell triggering induced by activating HLA class I-specific NK receptors (NKR) or on TCR alpha beta-mediated T cell activation. CD3-CD16+ NK cell clones expressing activating NKR (either CD94 or p50) were analyzed in a redirected killing assay using P815 target cells and appropriate mAb. A strong target cell lysis was detected in the presence of anti-NKR or anti-CD16 mAb alone. Addition of anti-p40 mAb resulted in a strong inhibition of both anti-NKR or anti-CD16 mAb-induced cytolysis. mAb specific for either CD45 or lymphocyte function associated antigen-1 did not exert any inhibitory effect in the same experimental system. Free intracellular calcium ([Ca2+]i) increase induced by mAb cross-linking of activating CD94 or p50 was inhibited by simultaneous engagement of p40 molecules, but not of other NK surface molecules including CD44 and CD56. In addition, cross-linking of p40 molecules strongly inhibited the CD94-induced tumor necrosis factor-alpha and IFN-gamma production. Analysis of TCR alpha beta or gamma delta T cell clones revealed that the engagement of p40 molecules, using specific mAb, induced some degree of inhibition only on anti-V beta (but not anti-V delta or anti-CD3) mAb-induced cytotoxicity. On the other hand, the p40 molecule engagement prevented T cell proliferation induced by either anti-V beta 8 or anti-V delta 2 mAb. A similar inhibitory effect was found on the IL-2-induced NK cell proliferation. Taken together, our present findings suggest that p40 may play a role in the regulation of NK and T lymphocyte activation and proliferation.
authors.affiliation: Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Poggi
authors.forename: E
authors.initials: E
authors.lastname: Tomasello
authors.forename: V
authors.initials: V
authors.lastname: Revello
authors.forename: L
authors.initials: L
authors.lastname: Nanni
authors.forename: P
authors.initials: P
authors.lastname: Costa
authors.forename: L
authors.initials: L
authors.lastname: Moretta
mesh_terms: D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006680:HLA Antigens / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D004268:DNA-Binding Proteins; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C077214:L1Hs-encoded protein p40, human; D007371:Interferon-gamma; D002118:Calcium