Interplay of T-cell receptor and interleukin-2 signalling in Vγ2Vδ2 T-cell cytotoxicity.
Human peripheral blood Vγ2Vδ2 T cells are important for host defence and tumour immunity. Their unusual T-cell receptor (TCR) recognizes small molecule phosphoantigens; stimulated cells produce inflammatory cytokines and are potently cytotoxic for a variety of tumours. However, molecular mechanisms linking phosphoantigen stimulation and cytotoxicity are incompletely understood. We know that isopentenyl pyrophosphate (IPP) activates mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/Erk) and phosphoinositide 3-kinase (PI-3K)/Akt pathways; specific inhibition of Erk or Akt significantly impairs the functional response to IPP. We now show that interleukin-2 also activates MEK/Erk and PI-3K/Akt pathways but on its own, fails to induce cytokine expression or cytotoxicity. Hence, MEK/Erk and PI-3K/Akt activation are necessary but not sufficient to induce effector responses in Vγ2Vδ2 T cells and a TCR-dependent signal is still required for tumour cell killing. Cyclosporin A, an inhibitor of calcineurin, blocked calcium-dependent nuclear translocation of nuclear factor of activated T cell (NFAT) and significantly reduced IPP-induced cytokine production, degranulation and cytotoxicity. The IPP-induced calcium mobilization and NFAT translocation were necessary to activate Vγ2Vδ2 effector functions; interleukin-2, acting on the MEK/Erk pathway, regulated the strength of these responses. The TCR has a specific role in Vγ2Vδ2 T-cell killing of tumour cells, which is distinct from its role in triggering cellular proliferation in response to phosphoantigens.
Li
Haishan
H
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
David Pauza
C
C
D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D045782:Hemiterpenes / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016572:Cyclosporine; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D045782:Hemiterpenes; D007376:Interleukin-2; D009943:Organophosphorus Compounds; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016692:Receptors, Antigen, T-Cell, gamma-delta; C004809:isopentenyl pyrophosphate