Differential Tumor Surveillance by Natural Killer (Nk) and Nkt Cells

Smyth, Mark J.; Thia, Kevin; Street, Shayna E.A.; Cretney, Erika; Trapani, Joseph A.; Taniguchi, Masaru; Kawano, Tetsu; Pelikan, Sonja B.; Crowe, Nadine Y.; Godfrey, Dale I.

doi:10.1084/jem.191.4.661

Cited by 719 publications

(544 citation statements)

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“…iNKT cells are abundant in the liver and rapidly secrete large amounts of immunoregulatory cytokines such as IFN-g and IL-4 after stimulation through their TCR [35][36][37][38][39][40]. Administration of a-GalCer to mice causes rapid release of various cytokines from iNKT cells, which participate in the regulation of various diseases, including tumor rejection and prevention of autoimmune diseases [41][42][43][44][45][46].Although a-GalCer can enhance host resistance against some microbial pathogens [47-55], it remains elusive whether a-GalCer enhances protective immunity against intracellular bacteria.We have recently shown that listeriosis is ameliorated in iNKT-cell-deficient mice [56]. This finding argues against a protective role of iNKT cells in listeriosis.…”

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confidence: 99%

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

Emoto

Yoshizawa

et al. 2010

Eur J Immunol

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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 ...

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confidence: 99%

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

Emoto

Yoshizawa

et al. 2010

Eur J Immunol

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“…Identification of the NKT cell subsets that might specialise in Th1 versus Th2 functions has not been thoroughly investigated. The secretion of Th1 and Th2 cytokines by NKT cells is thought to underlie the regulatory properties of these cells (5,6), which suggests a flexible role for NKT cells in immunoregulation, although a clear difference in cytokine production between NKT cell subsets cannot be resolved at this time. Although expression profiles of Th1/Th2 cytokines between mice and humans differ, the question remains as to how these cytokines lead to a regulated immune response in vivo.…”

Section: Introductionmentioning

confidence: 99%

EBV-Induced Human CD8+ NKT Cells Synergise CD4+ NKT Cells Suppressing EBV-Associated Tumours Upon Induction of Th1-Bias

Xiao

Zhou

et al. 2009

Cell Mol Immunol

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“…To test this point, mice were inoculated with B16F10 melanoma cells which are known to be controlled by NK cells. 27,28 While C57BL/6, C57BL/6 × Ly5.1 C14R and Ly5.1 (Jax, 2017) mice were able to largely control tumor growth as measured by the number of primary lung tumors 14 days after tumor inoculation (Figure 4C and D), mice that expressed the NKp46 C14R single point mutation developed significantly more lung metastases, a condition that was accompanied by respiratory distress. These mice also presented metastases in other organs such as the kidney, liver and bone marrow (SI Appendix, Figure S5 D ), a phenotype which was similar to that observed in Mcl-1 fl/fl Ncr1 iCre mice in which NCR + cells are conditionally ablated 29 (Figure 4C and D and SI Appendix, Figure S5D).…”

Section: Resultsmentioning

confidence: 99%

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

et al. 2018

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NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.SignificanceInnate lymphoid cells (ILCs) play important roles in immune protection. Various subsets of ILCs express the activating receptor NKp46 which is capable of recognizing pathogen derived and tumor ligands and is necessary for immune protection. Here, we describe a spontaneous point mutation in the signal peptide of the NKp46 protein in congenic Ly5.1 mice which are widely used for tracking cells in vivo. This Ncr1 C14R mutation impairs NKp46 surface expression resulting in destabilization of Ncr1 and accumulation of NKp46 in the endoplasmic reticulum. Loss of stable NKp46 expression impaired the maturation of NKp46+ ILCs and altered the expression of TRAIL and T-bet in ILC1 and ILC3, respectively.

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Differential Tumor Surveillance by Natural Killer (Nk) and Nkt Cells

Cited by 719 publications

References 47 publications

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

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

EBV-Induced Human CD8+ NKT Cells Synergise CD4+ NKT Cells Suppressing EBV-Associated Tumours Upon Induction of Th1-Bias

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

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Differential Tumor Surveillance by Natural Killer (Nk) and Nkt Cells

Cited by 719 publications

References 47 publications

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

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

EBV-Induced Human CD8+ NKT Cells Synergise CD4+ NKT Cells Suppressing EBV-Associated Tumours Upon Induction of Th1-Bias

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

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

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