Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response

Lee, You Jeong; Wang, Haiguang; Starrett, Gabriel J.; Phuong, Vanessa; Jameson, Stephen C.; Hogquist, Kristin A.

doi:10.1016/j.immuni.2015.06.025

Cited by 237 publications

(283 citation statements)

References 53 publications

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“…Studies in germ-free mice suggest that the iNKT cell compartment can be shaped by CD1d-lipid signals in the enteral tract (11,25), and thus early-life exposure to cow's milkbased infant formula might similarly shape human mucosal iNKT cells in early life. In adult mice, orally delivered antigen activates iNKT cells in the gut (26), suggesting that exposure to dietary lipid antigens in adult life may also have consequences. Interestingly, it is unclear whether cows have iNKT cells (27), as their CD1d does not present the long-chain α-galactosylceramide commonly used as a tool in mice and humans (28).…”

Section: Discussionmentioning

confidence: 99%

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Brennan

Cheng

Pellicci

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glycolipid antigens recognized by αβ T-cell receptors (TCRs) drive the activation of invariant natural killer T (iNKT) cells, a specialized subset of innate T lymphocytes. Glycolipids with α-linked anomeric carbohydrates have been identified as potent microbial lipid antigens for iNKT cells, and their unusual α-anomeric linkage has been thought to define a “foreign” lipid antigen motif. However, mammals use endogenous lipids to select iNKT cells, and there is compelling evidence for iNKT cell responses in various types of sterile inflammation. The nature of endogenous or environmental lipid antigens encountered by iNKT cells is not well defined. Here, we sought to identify lipid antigens in cow’s milk, a prominent part of the human diet. We developed a method to directly capture lipid antigens within CD1d–lipid–TCR complexes, while excluding CD1d bound to nonantigenic lipids, followed by direct biochemical analysis of the lipid antigens trapped at the TCR–CD1d interface. The specific antigens captured by this “TCR trap” method were identified as α-linked monohexosylceramides by mass spectrometry fragmentation patterns that distinguished α- from β-anomeric monohexosylceramides. These data provide direct biochemical evidence for α-linked lipid antigens from a common dietary source.

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Section: Discussionmentioning

confidence: 99%

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Brennan

Cheng

Pellicci

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Although iNKT cell subsets preferentially secrete Th1, Th2, or Th17 cytokines, this response is not absolute given that many iNKT cells produce both IL-4 and IFN-g, and the extent of their activation is influenced by their location within lymphoid organs (53). Given that our set of TCRs induced different frequency of iNKT cell subsets, we predicted that they would also polarize the iNKT cytokine response upon Ag stimulation.…”

Section: The Inkt Tcr Does Not Control the Quality Of The Response Inmentioning

confidence: 99%

Discrete TCR Binding Kinetics Control Invariant NKT Cell Selection and Central Priming

Tleugabulova

Escalante

Deng

et al. 2016

The Journal of Immunology

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Invariant NKT (iNKT) cells develop and differentiate in the thymus, segregating into iNKT1/2/17 subsets akin to Th1/2/17 classical CD4+ T cells; however, iNKT TCRs recognize Ags in a fundamentally different way. How the biophysical parameters of iNKT TCRs influence signal strength in vivo and how such signals affect the development and differentiation of these cells are unknown. In this study, we manipulated TCRs in vivo to generate clonotypic iNKT cells using TCR retrogenic chimeras. We report that the biophysical properties of CD1d–lipid–TCR interactions differentially impacted the development and effector differentiation of iNKT cells. Whereas selection efficiency strongly correlated with TCR avidity, TCR signaling, cell–cell conjugate formation, and iNKT effector differentiation correlated with the half-life of CD1d–lipid–TCR interactions. TCR binding properties, however, did not modulate Ag-induced iNKT cytokine production. Our work establishes that discrete TCR interaction kinetics influence iNKT cell development and central priming.

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“…This imaging/analysis pipeline allows multiplex phenotypic identification and quantification of cells directly in tissues, akin to in situ flow cytometry. This technique has been used to study the composition, distribution, and function of densely packed cells with complex phenotypes and morphology in tissue sections (13)(14)(15)(16)(17)(18)(19)(20)(21). Even for cell types with relatively simple morphology, such as T and B lymphocytes, histo-cytometry requires a high degree of spatial signal resolution, achieved with high numerical aperture (N.A.)…”

mentioning

confidence: 99%

Multiplex, quantitative cellular analysis in large tissue volumes with clearing-enhanced 3D microscopy (C _e 3D)

Germain

Gerner

2017

Proc. Natl. Acad. Sci. U.S.A.

221

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Organ homeostasis, cellular differentiation, signal relay, and in situ function all depend on the spatial organization of cells in complex tissues. For this reason, comprehensive, high-resolution mapping of cell positioning, phenotypic identity, and functional state in the context of macroscale tissue structure is critical to a deeper understanding of diverse biological processes. Here we report an easy to use method, clearing-enhanced 3D (C e 3D), which generates excellent tissue transparency for most organs, preserves cellular morphology and protein fluorescence, and is robustly compatible with antibody-based immunolabeling. This enhanced signal quality and capacity for extensive probe multiplexing permits quantitative analysis of distinct, highly intermixed cell populations in intact C e 3D-treated tissues via 3D histo-cytometry. We use this technology to demonstrate large-volume, high-resolution microscopy of diverse cell types in lymphoid and nonlymphoid organs, as well as to perform quantitative analysis of the composition and tissue distribution of multiple cell populations in lymphoid tissues. Combined with histo-cytometry, C e 3D provides a comprehensive strategy for volumetric quantitative imaging and analysis that bridges the gap between conventional section imaging and disassociation-based techniques.tissue clearing | quantitative microscopy | histo-cytometry | immune system M ajor physiological processes rely on the precise positioning of diverse cell types in specific anatomical locations. Such organization allows exposure of cells to appropriate tissue microenvironments that shape their differentiation, promote appropriate cell-cell communication events, and collectively define the global properties of the whole organ. Understanding these structure-function relationships requires a detailed mapping of both the large-scale organization and fine-grained molecular and cellular composition of complex tissues.The majority of information on such processes comes from microscopic imaging of relatively thin (5-20 μm) "2D" tissue crosssections, examining several markers of interest to visualize a limited number of cell populations with respect to a tissue's representative structural elements. Although providing an excellent framework for understanding general features and the respective positioning of well-represented cell types, such data lack information on 3D organization, being particularly limiting for irregular structures such as the vasculature, airways, nervous tissue, inflamed sites, tumors, or reactive lymph nodes. Furthermore, detection and analysis of rare cellular events requires imaging of a large number of disconnected sections, which introduces possible image selection bias and suffers from the potential omission of key physiological landmarks located just outside of the sampled area. Finally, many cell types require simultaneous visualization of multiple phenotypic markers for correct subset identification, making interpretation of cell composition within tissues problematic without the use...

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Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response

Cited by 237 publications

References 53 publications

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Discrete TCR Binding Kinetics Control Invariant NKT Cell Selection and Central Priming

Multiplex, quantitative cellular analysis in large tissue volumes with clearing-enhanced 3D microscopy (C _e 3D)

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Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response

Cited by 237 publications

References 53 publications

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

Discrete TCR Binding Kinetics Control Invariant NKT Cell Selection and Central Priming

Multiplex, quantitative cellular analysis in large tissue volumes with clearing-enhanced 3D microscopy (C e 3D)

Contact Info

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Multiplex, quantitative cellular analysis in large tissue volumes with clearing-enhanced 3D microscopy (C _e 3D)