CD158 receptor controls cytotoxic T-lymphocyte susceptibility to tumor-mediated activation-induced cell death by interfering with Fas signaling.
Renal cell carcinoma-infiltrating lymphocytes express killer cell immunoglobulin-like receptors (KIRs) that inhibit antitumor CD8+ T-cell functions and may contribute to local self-tolerance. In the present study, to better examine the functional consequences of KIR engagement on CTL-tumor interactions, we investigated the influence of KIR2DL1/CD158a on CTL survival. We show that both KIR+ and KIR- antigen-specific CTLs express Fas and Fas ligand and were susceptible to activation-induced cell death (AICD) triggered by coated anti-CD3 monoclonal antibodies. In KIR+ CTLs, anti-CD158a monoclonal antibodies partially inhibited anti-CD3-induced AICD. Interestingly, T-cell receptor activation by cognate tumor cells induced apoptosis in KIR+ CTLs but not in KIR- CTLs. In addition, co-engagement of T-cell receptors and KIRs by tumor cells decreased tumor-mediated CTL apoptosis. Blocking the interaction of KIR/HLA-Cw4 resulted in the restoration of tumor-induced AICD. Most importantly, our data indicate that KIR engagement affected two proximal events of Fas signaling pathway, a sustained c-FLIP-L induction and a decrease in caspase 8 activity. These studies provide evidence that tumor cells selectively favor the local persistence of nonfunctional KIR+ CTLs by promoting their survival.
Gati
Asma
A
Institut National de la Santé et de la Recherche Médicale (INSERM) U487, Institut Fédératif de Recherche 54, 94805 Villejuif, France.
Guerra
Nadia
N
Gaudin
Catherine
C
Da Rocha
Sylvie
S
Escudier
Bernard
B
Lécluse
Yann
Y
Bettaieb
Ali
A
Chouaib
Salem
S
Caignard
Anne
A
D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D017252:CD3 Complex / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D015536:Down-Regulation; D006801:Humans; D007680:Kidney Neoplasms / Q000276:immunology; D008213:Lymphocyte Activation; D011971:Receptors, Immunologic / Q000276:immunology*; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D019014:fas Receptor