Activation of human dendritic cells by the PorA protein of Neisseria meningitidis

Authors

  • Tamara Al-Bader,

    1. Dermatopharmacology Unit, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
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  • Keith A. Jolley,

    1. Molecular Microbiology and Infection, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
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    • Present address: Wellcome Trust Centre for the Epidemiology of Infectious Disease, Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

  • Holly E. Humphries,

    1. Molecular Microbiology and Infection, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
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  • Judith Holloway,

    1. Department of Child Health, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
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  • John E. Heckels,

    1. Molecular Microbiology and Infection, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
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  • Amanda E. Semper,

    1. Dermatopharmacology Unit, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
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  • Peter S. Friedmann,

    1. Dermatopharmacology Unit, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
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  • Myron Christodoulides

    Corresponding author
    1. Molecular Microbiology and Infection, Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton SO16 6YD, UK.
      E-mail mc4@soton.ac.uk; Tel. (+44) 2380 798896; Fax (+44) 2380 796995.
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E-mail mc4@soton.ac.uk; Tel. (+44) 2380 798896; Fax (+44) 2380 796995.

Summary

The major porin proteins present in the outer membrane of Neisseria meningitidis, the causative agent of life-threatening meningitis and septicaemia, are believed to have potent immunostimulatory effects. In this study, the interactions between human monocyte-derived dendritic cells (mo-DC) and the PorA porin were investigated, in order to reveal the role of this protein in promoting innate and adaptive immune responses. Recombinant (r)PorA induced mo-DC maturation, as reflected by reduced receptor-mediated endocytosis, increased production of the chemokines IL-8, RANTES, MIP-1α and MIP-1β and augmented expression of the surface markers CD40, CD54, CD80, CD86 and major histocompatibility complex class II molecules. However, rPorA induced either low level or no significant secretion of pro-inflammatory cytokines from mo-DC. The protein potently augmented the capacity of mo-DC to activate both allogeneic CD4+ memory T-cells and CD4+RA+ naïve T-cells. In addition, rPorA appeared to inhibit the production of IL-12p70 that follows from the interaction between CD40 on the mo-DC and CD40-ligand on T-cells, thereby directing T-cell differentiation towards a Th2 type response. These data demonstrate that PorA is involved in DC activation and in influencing the nature of the T-helper immune response, which are important properties for generating antibody responses required for protective immunity against meningococci and for determining the immuno-adjuvant effects of this protein.

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