CD1d-Dependent B-Cell Help by NK-Like T Cells Leads to Enhanced and Sustained Production of Bacillus anthracis Lethal Toxin-Neutralizing Antibodies

Abstract

The current Bacillus anthracis vaccine consists largely of protective antigen (PA), the protein of anthrax toxin that mediates entry of edema factor (EF) or lethal factor (LF) into cells. PA induces protective antibody (Ab)-mediated immunity against Bacillus anthracis but has limited efficacy and duration. We previously demonstrated that activation of CD1d-restricted natural killer-like T cells (NKT) with a CD1d-binding glycolipid led to enhanced Ab titers specific for foreign antigen (Ag). We therefore tested the hypothesis that activation of NKT cells with the CD1d ligand (␣-galactosylceramide [␣-GC]) at the time of immunization improves PA-specific Ab responses. We observed that ␣-GC enhanced PA-specific Ab titers in C57BL/6 mice. In CD1d ؊/؊ mice deficient in type I and type II NKT cells the anti-PA Ab response was diminished. In J␣281 ؊/؊ mice expressing CD1d but lacking type I ␣-GC-reactive NKT cells, ␣-GC did not enhance the Ab response. In vitro neutralization assays were performed and showed that the Ab titers correlated with protection of macrophages against anthrax lethal toxin (LT). The neutralization capacity of the Ab was further tested in lethal challenge studies, which revealed that NKT activation leads to enhanced in vivo protection against LT. Anti-PA Ab titers, neutralization, and protection were then measured over a period of several months, and this revealed that NKT activation leads to a sustained protective Ab response. These results suggest that NKT-activating CD1d ligands could be exploited for the development of improved vaccines for Bacillus anthracis that increase not only neutralizing Ab titers but also the duration of the protection afforded by Ab.

Retinoic Acid and α-Galactosylceramide Differentially Regulate B Cell ActivationIn Vitroand Augment Antibody ProductionIn Vivo

“…Several recent reports provide evidence that ␣GalCer and its analog could be an effective adjuvant in the immunization protocol (8,18,20). With the understanding of the interaction of RA and ␣GalCer, the combination may be promising for improving vaccine effectiveness in the future.…”

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

“…Preclinical results highlight the efficacy and attractiveness of the use of vaccine containing αGalCer simply mixed with protein Ags derived from a variety of infectious pathogens, to activate noncognate B-cell help by iNKT cells and induce efficient protective humoral responses and long-lasting memory through mucosal and parenteral administration routes [43,[46][47][48][49].…”

Adjuvant effects of therapeutic glycolipids administered to a cohort of NKT cell-diverse pigs

“…Also, intratracheal inoculation with the NKT superagonist alpha-galactosylceramide (␣GC) stimulates NKT cell activation in pig lungs (Renukaradhya et al, 2011). Previous reports have demonstrated that NKT cell superagonisits can protect mice from several pathogens that affect swine, including influenza (Ho et al, 2008), Pseudomonas aeruginosa (Minagawa et al, 2005;Nieuwenhuis et al, 2002), Streptococcus pneumoniae (Nakamatsu et al, 2007), Mycobacterium tuberculosis (Chackerian et al, 2002;Sada-Ovalle et al, 2010), Listeria monocytogenes (Emoto et al, 2010), Staphylococcus aureus (Lin et al, 2010), cytomegalovirus (van Dommelen et al, 2003), Trypanosoma cruzi (Duthie and Kahn, 2002), Japanese encephalitis virus (Lin et al, 2010) and Bacillus anthrax (Devera et al, 2010). In addition, the adjuvant effects of NKT cell superagonists have been exploited in mice to improve vaccines against microorganisms that also infect pigs, including influenza (Guillonneau et al, 2009;Ko et al, 2005;Kopecky-Bromberg et al, 2009;Lee et al, 2011;Youn et al, 2007), M. tuberculosis (Venkataswamy et al, 2009) and B. anthrax (Devera et al, 2010).…”