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: 39.33).
02/2007; 25(1):297-336. DOI: 10.1146/annurev.immunol.25.022106.141711
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.
Available from: Pooja Arora
- "CD1d-restricted iNKT cells are an intriguing subset of T cells that function at the inferface between innate and adaptive immune responses. They are important for mammalian immunity to microbial infections, and also are likely to contribute to autoimmune disorders and responses to cancers (Brennan et al., 2013; Bendelac et al., 2007). The ability to activate these cells by a single administration of a glycolipid agonist makes them an attractive target for development of immunotherapeutic applications (McEwen-Smith et al., 2015). "
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ABSTRACT: Invariant natural killer T (iNKT) cells recognize glycolipid antigens presented by CD1d, an antigen presenting protein structurally similar to MHC class I. Stimulation of iNKT cells by glycolipid antigens can induce strong immune responses in vivo, with rapid production of a wide variety of cytokines including those classically associated with either T helper type 1 (Th1) or type 2 (Th2) responses. Alterations in the lipid tails or other portions of CD1d-presented glycolipid ligands can bias the iNKT response towards production of predominantly Th1 or Th2 associated cytokines. However, the mechanism accounting for this structure-activity relationship remains controversial. The Th1-biasing glycolipids have been found to consistently form complexes with CD1d that preferentially localize to plasma membrane cholesterol rich microdomains (lipid rafts), whereas CD1d complexes formed with Th2-biasing ligands are excluded from these microdomains. Here we show that neutralization of endosomal pH enhanced localization of CD1d complexes containing Th2-biasing glycolipids to plasma membrane lipid rafts of antigen presenting cells (APC). Transfer of APCs presenting these "stabilized" CD1d/αGC complexes into mice resulted in immune responses with a more prominent Th1-like bias, characterized by increased NK cell transactivation and interferon-γ production. These findings support a model in which low endosomal pH controls stability and lipid raft localization of CD1d-glycolipid complexes to regulate the outcome of iNKT cell mediated responses.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Chemistry and Physics of Lipids 08/2015; 191:75-83. DOI:10.1016/j.chemphyslip.2015.08.010 · 2.42 Impact Factor
Available from: Sung Won Lee
- "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 . 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 · 2.30 Impact Factor
Available from: Vivek Chandra
- "The selection process permits the developmental progression of a selected group of adaptive T-lineage cells that have acquired a TCR with moderate affinity for major histocompatibility complex (MHC) class II (CD4 single positive [CD4SP]) or class I (CD8SP) associated with self-antigens (Klein et al. 2014). On the other hand, innate T-lineage cells are selected by CD1 for invariant natural killer T (iNKT) cells and by MHCrelated protein MR1 for mucosal-associated invariant T lymphocytes (MAIT) (Bendelac et al. 2007; Gold and Lewinsohn 2013) Adaptive B and T cells express an enormously diverse antigen receptor repertoire. They maintain a naı¨ve lymphoid cell state until they encounter invading pathogens, upon which they expand and differentiate into effector cells. "
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ABSTRACT: It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naïve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a TFH transcription signature. We show that Id2 and Id3 acted upstream of the Hif1a/Foxo/AKT/mTORC1 pathway as well as the c-myc/p19Arf module to control cellular expansion. We found that mice depleted for Id2 and Id3 expression developed colitis and αβ T-cell lymphomas. Lymphomas depleted for Id2 and Id3 expression displayed elevated levels of c-myc, whereas p19Arf abundance declined. Transcription signatures of Id2- and Id3-depleted lymphomas revealed similarities to genetic deficiencies associated with Burkitt lymphoma. We propose that, in response to antigen receptor and/or cytokine signaling, the E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to control cellular expansion and homeostatic proliferation.
© 2015 Miyazaki et al.; Published by Cold Spring Harbor Laboratory Press.
Genes & Development 02/2015; 29(4):409-25. DOI:10.1101/gad.255331.114 · 10.80 Impact Factor
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