Butyrophilin 3A/CD277-Dependent Activation of Human γδ T Cells: Accessory Cell Capacity of Distinct Leukocyte Populations.
Human Vγ9Vδ2 T cells recognize in a butyrophilin 3A/CD277-dependent way microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) or endogenous pyrophosphates (isopentenyl pyrophosphate [IPP]). Nitrogen-bisphosphonates such as zoledronic acid (ZOL) trigger selective γδ T cell activation because they stimulate IPP production in monocytes by inhibiting the mevalonate pathway downstream of IPP synthesis. We performed a comparative analysis of the capacity of purified monocytes, neutrophils, and CD4 T cells to serve as accessory cells for Vγ9Vδ2 T cell activation in response to three selective but mechanistically distinct stimuli (ZOL, HMBPP, agonistic anti-CD277 mAb). Only monocytes supported γδ T cell expansion in response to all three stimuli, whereas both neutrophils and CD4 T cells presented HMBPP but failed to induce γδ T cell expansion in the presence of ZOL or anti-CD277 mAb. Preincubation of accessory cells with the respective stimuli revealed potent γδ T cell-stimulating activity of ZOL- or anti-CD277 mAb-pretreated monocytes, but not neutrophils. In comparison with monocytes, ZOL-pretreated neutrophils produced little, if any, IPP and expressed much lower levels of farnesyl pyrophosphate synthase. Exogenous IL-18 enhanced the γδ T cell expansion with all three stimuli, remarkably also in response to CD4 T cells and neutrophils preincubated with anti-CD277 mAb or HMBPP. Our study uncovers unexpected differences between monocytes and neutrophils in their accessory function for human γδ T cells and underscores the important role of IL-18 in driving γδ T cell expansion. These results may have implications for the design of γδ T cell-based immunotherapeutic strategies.
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Patrik Theodor
0000-0002-8954-3516
PT
Nerdal
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Christian
0000-0002-7669-3806
C
Peters
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Hans-Heinrich
HH
Oberg
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
Hristo
H
Zlatev
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Marcus
0000-0002-3824-9923
M
Lettau
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.|Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Elgar Susanne
ES
Quabius
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
Sofia
0000-0002-4368-4866
S
Sousa
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Daniel
0000-0002-5669-1213
D
Gonnermann
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
Seppo
S
Auriola
Laboratoire d'Immunologie des Tumeurs, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM, U1068, F-13009 Marseille, France.|CNRS, UMR7258, F-13009 Marseille, France.|Institut Paoli-Calmettes, F-13009 Marseille, France.|Aix-Marseille University, UM 105, F-13284 Marseille, France; and.
Daniel
0000-0003-1299-4113
D
Olive
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland.|Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
Jorma
0000-0001-8752-6862
J
Määttä
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
Ottmar
0000-0002-9612-8900
O
Janssen
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein, D-24105 Kiel, Germany; dietrich.kabelitz@uksh.de.
Dieter
D
Kabelitz
D019138:Antibodies, Blocking / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000071797:Butyrophilins / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004164:Diphosphonates / Q000276:immunology; D051228:Geranyltranstransferase / Q000378:metabolism; D045782:Hemiterpenes / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000276:immunology; D020382:Interleukin-18 / Q000378:metabolism; D008213:Lymphocyte Activation; D008798:Mevalonic Acid / Q000378:metabolism; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010755:Organophosphates / Q000276:immunology; D009943:Organophosphorus Compounds / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D000077211:Zoledronic Acid
C467061:4-hydroxy-3-methyl-2-butenyl diphosphate; D019138:Antibodies, Blocking; D015703:Antigens, CD; C558381:BTN3A1 protein, human; D000071797:Butyrophilins; D004164:Diphosphonates; D045782:Hemiterpenes; D007093:Imidazoles; D020382:Interleukin-18; D010755:Organophosphates; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; C004809:isopentenyl pyrophosphate; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase; D008798:Mevalonic Acid