Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2014 Oct 28:5:543.
doi: 10.3389/fimmu.2014.00543. eCollection 2014.

NKT cell networks in the regulation of tumor immunity

Faith C Robertson  1 , Jay A Berzofsky  1 , Masaki Terabe  1
Affiliations
Review

NKT cell networks in the regulation of tumor immunity

Faith C Robertson et al. Front Immunol. .

Abstract

CD1d-restricted natural killer T (NKT) cells lie at the interface between the innate and adaptive immune systems and are important mediators of immune responses and tumor immunosurveillance. These NKT cells uniquely recognize lipid antigens, and their rapid yet specific reactions influence both innate and adaptive immunity. In tumor immunity, two NKT subsets (type I and type II) have contrasting roles in which they not only cross-regulate one another, but also impact innate immune cell populations, including natural killer, dendritic, and myeloid lineage cells, as well as adaptive populations, especially CD8(+) and CD4(+) T cells. The extent to which NKT cells promote or suppress surrounding cells affects the host's ability to prevent neoplasia and is consequently of great interest for therapeutic development. Data have shown the potential for therapeutic use of NKT cell agonists and synergy with immune response modifiers in both pre-clinical studies and preliminary clinical studies. However, there is room to improve treatment efficacy by further elucidating the biological mechanisms underlying NKT cell networks. Here, we discuss the progress made in understanding NKT cell networks, their consequent role in the regulation of tumor immunity, and the potential to exploit that knowledge in a clinical setting.

Keywords: NKT cell; NKT cell subsets; immune network; immune regulation; tumor immunology.

PubMed Disclaimer

Figures

Figure 1
Figure 1
NKT cell subsets. The natural killer T (NKT) cell population encompasses several phenotypically and functionally different subpopulations. Tissue location and surface markers (CD4, CD8, and NK1.1) are defining characteristics that broadly divide NKT cells and contribute to functionality. Differences in TCR rearrangements allow separation into two major subsets, type I and type II. Type I NKT cells express a semi-invariant TCRα chain, while type II NKT cells display a more diverse repertoire. It has been proposed that these NKT cell subsets recognize distinct lipid antigens. The prototypic antigen able to activate all type I NKT cells is α-GalCer. Type II NKT cells recognize a greater variety of antigens, one being sulfatide. Though these two subsets have been reported to recognize some common antigens, e.g., β-GlcCer, the biochemical structure is slightly different between the antigen recognized by type I versus type II NKT cells. Lastly, type I NKT cells are functionally heterogeneous. NKT1, NKT2, NKT17, NKTreg, NKTFH, and NKT10 subsets have been described. Overall, an in vivo NKT cell response likely depends on which subsets are activated.
Figure 2
Figure 2
Enhancement of tumor immunity. Upon antigenic stimulation, type I NKT cells produce copious amounts of IFN-γ, which helps activate both CD8+ T cells and DCs. NKT cells specifically induce DC maturation by engaging the CD1d-TCR complex and CD40–CD40L interaction. DCs then upregulate costimulatory receptors essential for the cross-priming of CD8+ T cells to promote adaptive immunity. Additionally, IL-12 production by DCs stimulates NK, NKT, and other T cells to produce more IFN-γ and the two cytokines together significantly impact the activation of downstream effector populations. Both type I and type II NKT cells have been shown to enhance proliferation of memory CD4+ T cells, which can help CD8+ T cells as well. NK and type I NKT cells are able to directly lyse tumor cells utilizing various mechanisms which include perforin, granzyme, and FasL. Type I NKT cell stimulation can also enhance tumor immunity by hindering immunosuppressive populations. Type I NKT cells regulate effects of type II and expansion of MDSCs. Tumor-induced inflammatory proteins like serum amyloid A 1 (SAA-1) have been shown to increase neutrophilic CD1d-dependent stimulation of type I NKT cells, which then mitigates the detrimental activity of suppressive neutrophils by hindering production of IL-10 and enhancing IL-12.
Figure 3
Figure 3
Suppression of tumor immunity. Activated type I NKT cells have been shown to support immunosuppressive Tregs through IL-2 production, and are then suppressed by Tregs in a cell-contact-dependent manner. Treg cells can then suppress CD8+ and CD4+ T cells and NK cells (not shown). Sulfatide-reactive type II NKT cells suppress CD8+ T cells and inhibit proliferation of naïve, but not memory, CD4+ T cells. Type II NKT cells also suppress Type I, and while the exact mechanism in cancer settings remains unknown, the mechanism in a con-A-induced hepatitis model is believed to involve pDCs. Type II NKT cell production of IL-13 functions with TNF-α from other cells to increase production of TGF-β by a CD11b+Gr1+ population known as myeloid-derived suppressor cells (MDSCs). MDSCs not only directly support tumor growth with TGF-β production but also suppress other immune cells (e.g., CD8+ T and NK cells), feed into an autocrine loop to enhance development of additional tumor-associated MDSCs, and aid in expansion of Tregs. When tumor-induced inflammatory proteins like SAA-1 stimulate suppressive IL-10 producing neutrophils, and type I NKT cells are not activated to alter that reaction, increased levels of IL-10 can induce Treg cells and potentiate further tumor growth.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med (2000) 192(5):741–54.10.1084/jem.192.5.741 - DOI - PMC - PubMed
    1. Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest (2004) 114(10):1379–88.10.1172/JCI23594 - DOI - PMC - PubMed
    1. Rhost S, Lofbom L, Rynmark BM, Pei B, Mansson JE, Teneberg S, et al. Identification of novel glycolipid ligands activating a sulfatide-reactive, CD1d-restricted, type II natural killer T lymphocyte. Eur J Immunol (2012) 42(11):2851–60.10.1002/eji.201142350 - DOI - PubMed
    1. Gapin L, Godfrey DI, Rossjohn J. Natural killer T cell obsession with self-antigens. Curr Opin Immunol (2013) 25(2):168–73.10.1016/j.coi.2013.01.002 - DOI - PMC - PubMed
    1. Terabe M, Berzofsky JA. The immunoregulatory role of type I and type II NKT cells in cancer and other diseases. Cancer Immunol Immunother (2014) 63(3):199–213.10.1007/s00262-013-1509-4 - DOI - PMC - PubMed
-