title: Increased expression of non-functional killer inhibitory receptor CD94 in CD8+ cells of myeloma patients.
abstract: Different MHC class I-specific killer inhibitory receptors (KIRs) are expressed in vivo by a minor fraction of activated memory CD8+ cells. It has been postulated that KIRs may 'fine-tune' specific responses by altering their threshold of activation by the TCR-CD3 complex. We have previously shown that, in multiple myeloma (MM) patients, a large fraction of peripheral blood CD8+ cells display the phenotype of chronically activated memory T cells (CD38+, HLA-DR+, CD25-, CD45R0+, CD28-). We investigated the expression of KIRs on MM T cells and determined their possible influence on cytolytic responses elicited via the CD3-TCR complex. The expression of CD94, a molecule that is part of a heterodimeric KIR recognizing the non-classical MHC surface HLA-E molecule, was almost threefold higher in MM T cells than in age-matched normal control subjects (P < 0.0001). CD94 expression was preferentially confined to CD8+ cells but not restricted to activated (HLA-DR+) and/or memory (CD45R0+) T cells. Unlike normal T cells, in which CD94 is assembled with glycoproteins of the NKG2 family to form functional receptors with activating or inhibitory properties, most CD94+ MM T cells were devoid of both the NKG2-A and NKG2-C glycoproteins detected in the inhibitory or activating form respectively. CD94 blockade did not significantly affect either T-cell proliferation or cytotoxic T-lymphocyte generation induced by the myeloma-derived cell lines NCI and RPMI 8226. Similarly, the cytolytic activity induced by direct anti-CD3-mediated targeting of MM T cells to FCR+ P815 target cells was unaffected by the addition of anti-CD94 and/or anti-NKG2-A/C monoclonal antibodies (mAbs). These data indicate that the large majority of MM CD8+ cells do not express a functional CD94 receptor. Thus, their ability to 'fine-tune' an appropriate immune response against tumour cells can be impaired.
authors.affiliation: Divisione di Ematologia dell'Universita' di Torino, Azienda Ospedaliera San Giovanni Battista di Torino, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Besostri
authors.forename: E
authors.initials: E
authors.lastname: Beggiato
authors.forename: A
authors.initials: A
authors.lastname: Bianchi
authors.forename: S
authors.initials: S
authors.lastname: Mariani
authors.forename: M
authors.initials: M
authors.lastname: Coscia
authors.forename: S
authors.initials: S
authors.lastname: Peola
authors.forename: M
authors.initials: M
authors.lastname: Foglietta
authors.forename: M
authors.initials: M
authors.lastname: Boccadoro
authors.forename: A
authors.initials: A
authors.lastname: Pileri
authors.forename: L
authors.initials: L
authors.lastname: Moretta
authors.forename: M
authors.initials: M
authors.lastname: Massaia
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis* / Q000276:immunology; D017252:CD3 Complex / Q000032:analysis; D016022:Case-Control Studies; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology*; D051920:NK Cell Lectin-Like Receptor Subfamily D
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D017252:CD3 Complex; D007376:Interleukin-2; C497869:KLRD1 protein, human; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D051920:NK Cell Lectin-Like Receptor Subfamily D; D017493:Leukocyte Common Antigens