Characterisation of the Immunomodulatory Effects of Meningococcal Opa Proteins on Human Peripheral Blood Mononuclear Cells and CD4+ T Cells.
Opa proteins are major surface-expressed proteins located in the Neisseria meningitidis outer membrane, and are potential meningococcal vaccine candidates. Although Opa proteins elicit high levels of bactericidal antibodies following immunisation in mice, progress towards human clinical trials has been delayed due to previous findings that Opa inhibits T cell proliferation in some in vitro assays. However, results from previous studies are conflicting, with different Opa preparations and culture conditions being used. We investigated the effects of various Opa+ and Opa- antigens from N. meningitidis strain H44/76 in a range of in vitro conditions using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells, measuring T cell proliferation by CFSE dilution using flow cytometry. Wild type recombinant and liposomal Opa proteins inhibited CD4+ T cell proliferation after stimulation with IL-2, anti-CD3 and anti-CD28, and these effects were reduced by mutation of the CEACAM1-binding region of Opa. These effects were not observed in culture with ex vivo PBMCs. Opa+ and Opa- OMVs did not consistently exert a stimulatory or inhibitory effect across different culture conditions. These data do not support a hypothesis that Opa proteins would be inhibitory to T cells if given as a vaccine component, and T cell immune responses to OMV vaccines are unlikely to be significantly affected by the presence of Opa proteins.
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Claire
C
Jones
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Manish
M
Sadarangani
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Susan
S
Lewis
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Isabelle
I
Payne
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Muhammad
M
Saleem
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Jeremy P
JP
Derrick
Oxford Vaccine Group, Department of Paediatrics, University of Oxford and NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.
Andrew J
AJ
Pollard
D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D001665:Binding Sites; D018106:CD28 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D015870:Gene Expression; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D007376:Interleukin-2 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008585:Meningitis, Meningococcal / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D022401:Meningococcal Vaccines / Q000096:biosynthesis; D009345:Neisseria meningitidis / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D014611:Vaccination
D000942:Antigens, Bacterial; D015703:Antigens, CD; D001425:Bacterial Outer Membrane Proteins; D018106:CD28 Antigens; D017252:CD3 Complex; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D007376:Interleukin-2; D022401:Meningococcal Vaccines; D020033:Protein Isoforms; D011994:Recombinant Proteins; C090348:Opa protein, Neisseria