The biology of NKT cells

Howard Hughes Medical Institute, Committee on Immunology, Department of Pathology University of Chicago, Chicago, Illinois 60637, USA.
Annual Review of Immunology (Impact Factor: 41.39). 02/2007; 25(1):297-336. DOI: 10.1146/annurev.immunol.25.022106.141711
Source: PubMed

ABSTRACT Recognized more than a decade ago, NKT cells differentiate from mainstream thymic precursors through instructive signals emanating during TCR engagement by CD1d-expressing cortical thymocytes. Their semi-invariant alphabeta TCRs recognize isoglobotrihexosylceramide, a mammalian glycosphingolipid, as well as microbial alpha-glycuronylceramides found in the cell wall of Gram-negative, lipopolysaccharide-negative bacteria. This dual recognition of self and microbial ligands underlies innate-like antimicrobial functions mediated by CD40L induction and massive Th1 and Th2 cytokine and chemokine release. Through reciprocal activation of NKT cells and dendritic cells, synthetic NKT ligands constitute promising new vaccine adjuvants. NKT cells also regulate a range of immunopathological conditions, but the mechanisms and the ligands involved remain unknown. NKT cell biology has emerged as a new field of research at the frontier between innate and adaptive immunity, providing a powerful model to study fundamental aspects of the cell and structural biology of glycolipid trafficking, processing, and recognition.

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    • "We found that CD69 expression increased upon IL32g stimulation in total NKT cells, CD1d- independent NKT cells, and CD1d-dependent iNKT cells (a-GC/ CD1d dimer þ CD3 þ ) in a dose-dependent manner (Fig. 1B). In addition to CD69, we investigated whether NKT cells produce IFNg and TNFa upon in vitro IL32g stimulation because NKT cells are one of the early producers of IFNg and TNFa [7]. As expected, production of IFNg and TNFa was enhanced in all of the NKT cells regardless of their CD1d-dependency (Fig. 1B). "
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    ABSTRACT: The inflammatory cytokine IL32γ acts on dendritic cells (DCs) to produce IL12 and IL6, which are involved in the differentiation of Th1 and Th17 cells. Natural killer (NK) and NKT cells play important roles in IL12-mediated adaptive immune responses, such as antitumor immunity. Herein we demonstrate the effect of IL32γ on the activation of NK and NKT cells. Upon IL32γ stimulation, splenic NK and NKT cells could be activated, and this activation was dependent on both IL12 and DCs, which was confirmed by using IL12p35 KO and CD11c-diphtheria toxin receptor transgenic mouse models. Furthermore, IL32γ could induce the production of proinflammatory cytokines by NKDCs, a subset of DCs expressing NK cell markers, known to enhance NKT cell function. Unlike conventional DCs, NKDCs produced IFNγ and TNFα rather than IL12 upon stimulation with IL32γ. Taken together, IL32γ will be useful as an adjuvant to boost the cytotoxicities of NK and NKT cells that play critical roles in antitumor immunity. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 04/2015; 461(1). DOI:10.1016/j.bbrc.2015.03.174 · 2.28 Impact Factor
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    • "While iNKT cells recognize a number of self [147] [148] and microbial [149] [150] [151] glycosphingolipids, most of our understanding of NKT cells comes from studies of murine and human iNKT cells stimulated with the xenogeneic glycolipid, agalactosylceramide (a-GC). Upon activation with a-GC in vitro, iNKT cells can kill target cells and secrete a diverse range of growth factors and cytokines [144] [145] [146]. Murine and human iNKT cells are unique in their ability to produce Th1 (IFN-c, TNF-a), Th2 (IL-4, IL- 5, IL-13), Th9 (IL-9), Th17 (IL-17A, IL-22) and regulatory T cell (IL- 10) cytokines, at times simultaneously [152] [153] [154] [155]. "
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    ABSTRACT: Unconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vγ9/Vδ2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vγ9/Vδ2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines. Copyright © 2015. Published by Elsevier Inc.
    Cellular Immunology 01/2015; 296(1). DOI:10.1016/j.cellimm.2015.01.008 · 1.87 Impact Factor
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    • "Medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) present self-antigen to thymocytes, whose TCR possess high avidity for self-antigen may die (negative selection) or differentiate into either natural occurring regulatory T (nTreg) cells or IL-17-producing CD4 þ T cells (nT H 17) [1,2]. High avidity for self-antigen also induces the differentiation of invariant natural killer T (iNKT) cell [3] and CD8aa þ intraepithelial lymphocyte [4]. The screening of autoreactive thymocytes is facilitated by the production of peripheral tissue specific antigens in mTECs and by the elevated expression of MHC and costimulatory molecules by some medullary APCs [5]. "
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    ABSTRACT: The interleukin-15 (IL-15) system is important for regulating both innate and adaptive immune responses, however, its role in autoimmune disease remained unclear. Here we found that Il15(-/-) and Il15ra(-/-) mice spontaneously developed late-onset autoimmune phenotypes. CD4(+) T cells of the knockout mice showed elevated autoreactivity as demonstrated by the induction of lymphocyte infiltration in the lacrimal and salivary glands when transferred into nude mice. The antigen-presenting cells in the thymic medullary regions expressed IL-15 and IL-15Rα, whose deficiency resulted in insufficient negative selection and elevated number of natural IL-17A-producing CD4(+) thymocytes. These findings reveal previously unknown functions of the IL-15 system in thymocyte development, and thus a new layer of regulation in T cell-mediated autoimmunity. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Journal of Autoimmunity 12/2014; 56. DOI:10.1016/j.jaut.2014.11.003 · 7.02 Impact Factor
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