Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Abstract

a-Galactosylceramide (a-GalCer) activates invariant (i)NKT cells, which in turn stimulate immunocompetent cells. Although activation of iNKT cells appears critical for regulation of immune responses, it remains elusive whether protection against intracellular bacteria can be induced by a-GalCer. Here, we show that a-GalCer treatment ameliorates murine listeriosis, and inhibits inflammation following Listeria monocytogenes infection. Liver infiltration of Gr-1 1 cells and c/d T cells was accelerated by a-GalCer treatment. Gr-1 1 cell and c/d T-cell depletion exacerbated listeriosis in a-GalCer-treated mice, and this effect was more pronounced after depletion of Gr-1 1 cells than that of c/d T cells. Although GM-CSF and IL-17 were secreted by NKT cells after a-GalCer treatment, liver infiltration of Gr-1 1 cells was not prevented by neutralizing mAb. In parallel to the numerical increase of CD11b 1 Gr-1 1 cells in the liver following a-GalCer treatment, CD11b À Gr-1 1 cells were numerically reduced in the bone marrow. In addition, respiratory burst in Gr-1 1 cells was enhanced by a-GalCer treatment. Our results indicate that a-GalCer-induced antibacterial immunity is caused, in part, by accelerated infiltration of Gr-1 1 cells and to a lesser degree of c/d T cells into the liver. We also suggest that the infiltration of Gr-1 1 cells is caused by an accelerated supply from the bone marrow.Key words: a-galactosylceramide . L. monocytogenes . NKT cell Supporting Information available online IntroductionListeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen, which causes disseminated infection in immunocompromised hosts [1]. Experimental murine listeriosis is instrumental in elucidating host defense mechanisms against intracellular bacteria. Cells of the innate immune system play a pivotal role as a first line of defense against L. monocytogenes [2-5] and among these, Gr-1 1 cells are central for the elimination of this pathogen at early stages of infection [6][7][8]. Numerous cytokines such as GM-CSF, IL-3, IL-6, IL-11, and SCF promote granulopoiesis by themselves and/or in concert with G-CSF [9,10]. G-CSF is indispensable for both steady-state and emergency granulopoiesis [11][12][13][14], and IL-17 regulates G-CSF secretion [9,10,[15][16][17][18]. In addition to Gr-1 1 cells, g/d T cells also participate in early protection against 1328L. monocytogenes infection [19][20][21][22]. The vast majority of L. monocytogenes organisms are trapped in the liver immediately after systemic infection [23] and hence, immunocompetent cells that reside in, and/or migrate into, the liver are critical for infection control.NKT cells represent a unique subset of T lymphocytes, which are characterized by the co-expression of NK cell markers such as NKR-P1B/C (NK1.1; CD161) [24]. In the mouse, the majority of NKT cells express an invariant (i) TCR composed of Va14/Ja18 gene segments, i.e. iNKT cells [24]. In contrast to conventional T cells, which recognize peptide antigens presented by polymorphic MHC ...

α-Galactosylceramide Promotes Killing ofListeria monocytogeneswithin the Macrophage Phagosome through Invariant NKT-Cell Activation

“…Since (i) iNKT cells secrete IFN-␥ in response to ␣-GalCer (6, 40), (ii) high levels of IFN-␥ were detected in peritoneal fluids of ␣-GalCer-treated C57BL/6, but not IL-15 Ϫ/Ϫ and SJL, mice, and (iii) iNKT cells were undetectable in the peritoneal cavity even at mRNA levels, we assume that IFN-␥ was derived from iNKT cells residing in an organ(s) other than the peritoneal cavity. Indeed, high numbers of IFN-␥-secreting cells were detected among liver iNKT cells 1 h after ␣-GalCer treatment (18). Consistent with this notion, IFN-␥ was detected in the peripheral blood of C57BL/6, but not IL-15…”

“…4A), although high numbers of ␣-GalCer/ CD1d tetramer-reactive T cells were detected in the livers of untreated C57BL/6 mice, and these became undetectable after ␣-GalCer treatment (Fig. 4A) (18,19). To verify whether iNKT cells were indeed absent in the peritoneal cavity, V␣14 mRNA expression in PC was analyzed.…”

“…We have recently described that ␣-GalCer ameliorates murine listeriosis, which is, in part, caused by accelerated infiltration of inflammatory cells into the liver (18), although iNKT cells themselves exacerbate disease (19). Because M play a central role in the elimination of L. monocytogenes, we considered the possibility that M participate in enhanced resistance to L. monocytogenes infection caused by ␣-GalCer treatment.…”

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).…”

Role of Natural Killer T Cells In Immunogenic Chemotherapy for Breast Cancer

“…Additionally, in recent studies it was shown that gd T cells directly responded to cytokines without any TCR engagement (25)(26)(27)(28), suggesting that the cytokine cas-cade elicited by a-GalCer could be strong enough to lead to gd T cell activation. Moreover, a-GalCer treatment has been recently shown to alleviate murine listeriosis, an effect partially lost after gd T cell depletion, suggesting a potential role of this population to achieve an optimal therapeutic effect of this lipid (29). Despite this finding, little is known about the precise functions of gd T cells as well as the mechanisms leading to their activation in the context of a-GalCer.…”