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Regulation of Anthrax Toxin-Specific Antibody Titers by Natural Killer T Cell-Derived IL-4 and IFNγ

By T. Scott Devera, Sunil K. Joshi, Lindsay M. Aye, Gillian A. Lang, Jimmy D. Ballard and Mark L. Lang


Activation of Natural Killer-like T cells (NKT) with the CD1d ligand α-GC leads to enhanced production of anthrax toxin protective Ag (PA)-neutralizing Abs, yet the underlying mechanism for this adjuvant effect is not known. In the current study we examined the role of Th1 and Th2 type responses in NKT-mediated enhancement of antibody responses to PA. First, the contribution of IL-4 and IFNγ to the production of PA-specific toxin-neutralizing Abs was examined. By immunizing C57Bl/6 controls IL-4−/− mice and IFNγ−/− mice and performing passive serum transfer experiments, it was observed that sera containing PA-specific IgG1, IgG2b and IgG2c neutralized toxin in vitro and conferred protection in vivo. Sera containing IgG2b and IgG2c neutralized toxin in vitro but were not sufficient for protection in vivo. Sera containing IgG1 and IgG2b neutralized toxin in vitro and conferred protection in vivo. IgG1 therefore emerged as a good correlate of protection. Next, C57Bl/6 mice were immunized with PA alone or PA plus a Th2-skewing α-GC derivative known as OCH. Neutralizing PA-specific IgG1 responses were modestly enhanced by OCH in C57Bl/6 mice. Conversely, IgG2b and IgG2c were considerably enhanced in PA/OCH-immunized IL-4−/− mice but did not confer protection. Finally, bone marrow chimeras were generated such that NKT cells were unable to express IL-4 or IFNγ. NKT-derived IL-4 was required for OCH-enhanced primary IgG1 responses but not recall responses. NKT-derived IL-4 and IFNγ also influenced primary and recall IgG2b and IgG2c titers. These data suggest targeted skewing of the Th2 response by α-GC derivatives can be exploited to optimize anthrax vaccination

Topics: Research Article
Publisher: Public Library of Science
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Provided by: PubMed Central

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  23. (2004). Immune responses to Bacillus anthracis protective antigen in patients with bioterrorismrelated cutaneous or inhalation anthrax.
  24. (2003). Impairment of dendritic cells and adaptive immunity by anthrax lethal toxin.
  25. (2005). Infection-induced marginal zone B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d.
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  27. (2005). Preferential T(h)2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo.
  28. (2004). Presentation of alphagalactosylceramide by murine CD1d to natural killer T cells is facilitated by plasma membrane glycolipid rafts.
  29. (1999). Presentation of protective antigen to the mouse immune system: immune sequelae.
  30. (2005). Protective antigen and toxin neutralization antibody patterns in anthrax vaccinees undergoing serial plasmapheresis.
  31. (2008). Requirement for CD1d expression by B cells to stimulate NKT cell-enhanced antibody production.
  32. (2009). Sequential B-cell epitopes of Bacillus anthracis lethal factor bind lethal toxin-neutralizing antibodies.
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  34. (2004). Synthetic glycolipid OCH prevents insulitis and diabetes in NOD mice.
  35. (2006). The CD1d-binding glycolipid alphagalactosylceramide enhances humoral immunity to T-dependent and Tindependent antigen in a CD1d-dependent manner.
  36. (1999). The IL-4 receptor: signaling mechanisms and biologic functions.
  37. (2009). The major neutralizing antibody responses to recombinant anthrax lethal and edema factors are directed to non-cross-reactive epitopes.
  38. (1998). The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice.
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