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  1. Article ; Online: Antigen-dependent versus -independent activation of invariant NKT cells during infection.

    Holzapfel, Keli L / Tyznik, Aaron J / Kronenberg, Mitchell / Hogquist, Kristin A

    Journal of immunology (Baltimore, Md. : 1950)

    2014  Volume 192, Issue 12, Page(s) 5490–5498

    Abstract: CD1d-reactive invariant NKT cells (iNKT) play a vital role in determining the characteristics of immune responses to infectious agents. Previous reports suggest that iNKT cell activation during infection can be: 1) solely driven by cytokines from innate ... ...

    Abstract CD1d-reactive invariant NKT cells (iNKT) play a vital role in determining the characteristics of immune responses to infectious agents. Previous reports suggest that iNKT cell activation during infection can be: 1) solely driven by cytokines from innate immune cells, 2) require microbial Ag, or 3) require self-Ag. In this study, we examined the role of Ag receptor stimulation in iNKT cells during several bacterial and viral infections. To test for Ag receptor signaling, Nur77(gfp) BAC transgenic mice, which upregulate GFP in response to Ag receptor but not inflammatory signals, were analyzed. iNKT cells in the reporter mice infected with mouse CMV produced IFN-γ but did not upregulate GFP, consistent with their reported CD1d-independent activation. However, two bacteria known to produce lipid Ags for iNKT cells induced GFP expression and cytokine production. In contrast, although Salmonella typhimurium was proposed to induce the presentation of a self-lipid, iNKT cells produced IFN-γ but did not upregulate GFP postinfection in vivo. Even in CD1d-deficient hosts, iNKT cells were still able to produce IFN-γ after S. typhimurium infection. Furthermore, although it has been proposed that endogenous lipid presentation is a result of TLR stimulation of APCs, injection of different TLR agonists led to iNKT cell IFN-γ but not increased GFP expression. These data indicate that robust iNKT cell responses to bacteria, as well as viruses, can be obtained in the absence of antigenic stimulation.
    MeSH term(s) Animals ; Antigen Presentation ; Antigens, Bacterial/immunology ; Antigens, CD1d/genetics ; Antigens, CD1d/immunology ; Lymphocyte Activation ; Mice ; Mice, Knockout ; Natural Killer T-Cells/immunology ; Natural Killer T-Cells/pathology ; Salmonella Infections/genetics ; Salmonella Infections/immunology ; Salmonella typhimurium/immunology
    Chemical Substances Antigens, Bacterial ; Antigens, CD1d ; CD1d antigen, mouse
    Language English
    Publishing date 2014-05-09
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1400722
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells.

    Lee, You Jeong / Holzapfel, Keli L / Zhu, Jinfang / Jameson, Stephen C / Hogquist, Kristin A

    Nature immunology

    2013  Volume 14, Issue 11, Page(s) 1146–1154

    Abstract: Invariant natural killer T cells (iNKT cells) can produce copious amounts of interleukin 4 (IL-4) early during infection. However, indirect evidence suggests they may produce this immunomodulatory cytokine in the steady state. Through intracellular ... ...

    Abstract Invariant natural killer T cells (iNKT cells) can produce copious amounts of interleukin 4 (IL-4) early during infection. However, indirect evidence suggests they may produce this immunomodulatory cytokine in the steady state. Through intracellular staining for transcription factors, we have defined three subsets of iNKT cells (NKT1, NKT2 and NKT17) that produced distinct cytokines; these represented diverse lineages and not developmental stages, as previously thought. These subsets exhibited substantial interstrain variation in numbers. In several mouse strains, including BALB/c, NKT2 cells were abundant and were stimulated by self ligands to produce IL-4. In those strains, steady-state IL-4 conditioned CD8(+) T cells to become 'memory-like', increased serum concentrations of immunoglobulin E (IgE) and caused dendritic cells to produce chemokines. Thus, iNKT cell-derived IL-4 altered immunological properties under normal steady-state conditions.
    MeSH term(s) Age Factors ; Animals ; Antigens, CD/genetics ; Antigens, CD/immunology ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; Cell Lineage/immunology ; Dendritic Cells/cytology ; Dendritic Cells/immunology ; GATA3 Transcription Factor/genetics ; GATA3 Transcription Factor/immunology ; Gene Expression Regulation ; Genetic Variation/immunology ; Immunity, Innate ; Immunoglobulin E/genetics ; Immunoglobulin E/immunology ; Immunologic Memory ; Immunophenotyping ; Interleukin-4/biosynthesis ; Interleukin-4/immunology ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/immunology ; Mice ; Natural Killer T-Cells/cytology ; Natural Killer T-Cells/immunology ; Promyelocytic Leukemia Zinc Finger Protein ; Species Specificity ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/immunology
    Chemical Substances Antigens, CD ; GATA3 Transcription Factor ; Gata3 protein, mouse ; Kruppel-Like Transcription Factors ; Promyelocytic Leukemia Zinc Finger Protein ; T-Box Domain Proteins ; T-box transcription factor TBX21 ; Zbtb16 protein, mouse ; Interleukin-4 (207137-56-2) ; Immunoglobulin E (37341-29-0)
    Language English
    Publishing date 2013-10-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2016987-5
    ISSN 1529-2916 ; 1529-2908
    ISSN (online) 1529-2916
    ISSN 1529-2908
    DOI 10.1038/ni.2731
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse.

    Moran, Amy E / Holzapfel, Keli L / Xing, Yan / Cunningham, Nicole R / Maltzman, Jonathan S / Punt, Jennifer / Hogquist, Kristin A

    The Journal of experimental medicine

    2011  Volume 208, Issue 6, Page(s) 1279–1289

    Abstract: The ability of antigen receptors to engage self-ligands with varying affinity is crucial for lymphocyte development. To further explore this concept, we generated transgenic mice expressing GFP from the immediate early gene Nr4a1 (Nur77) locus. GFP was ... ...

    Abstract The ability of antigen receptors to engage self-ligands with varying affinity is crucial for lymphocyte development. To further explore this concept, we generated transgenic mice expressing GFP from the immediate early gene Nr4a1 (Nur77) locus. GFP was up-regulated in lymphocytes by antigen receptor stimulation but not by inflammatory stimuli. In T cells, GFP was induced during positive selection, required major histocompatibility complex for maintenance, and directly correlated with the strength of T cell receptor (TCR) stimulus. Thus, our results define a novel tool for studying antigen receptor activation in vivo. Using this model, we show that regulatory T cells (T(reg) cells) and invariant NKT cells (iNKT cells) perceived stronger TCR signals than conventional T cells during development. However, although T(reg) cells continued to perceive strong TCR signals in the periphery, iNKT cells did not. Finally, we show that T(reg) cell progenitors compete for recognition of rare stimulatory TCR self-ligands.
    MeSH term(s) Animals ; Bone Marrow Cells/cytology ; Chromosomes, Artificial, Bacterial ; Flow Cytometry/methods ; Fluorescent Dyes/pharmacology ; Genes, Reporter ; Green Fluorescent Proteins/metabolism ; Inflammation ; Ligands ; Mice ; Mice, Transgenic ; Natural Killer T-Cells/cytology ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocytes, Regulatory/cytology ; Thymus Gland/cytology ; Up-Regulation
    Chemical Substances Fluorescent Dyes ; Ligands ; Receptors, Antigen, T-Cell ; Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2011-05-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20110308
    Database MEDical Literature Analysis and Retrieval System OnLINE

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