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  • The American Association of Immunologists  (17)
  • 1
    Online Resource
    Online Resource
    Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 195, No. 1 ( 2015-07-01), p. 145-155
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 195, No. 1 ( 2015-07-01), p. 145-155
    Abstract: Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4+FOXP3+Helios+ thymic-derived Tregs and CD4+FOXP3+Helios− T cells, followed by comparison with CD4+FOXP3−Helios− T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4+CD25+CD127lo/− T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226+TIGIT− population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1402381
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
    detail.hit.zdb_id: 1475085-5
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  • 2
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    Online Resource
    Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 177, No. 11 ( 2006-12-01), p. 7943-7949
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 177, No. 11 ( 2006-12-01), p. 7943-7949
    Abstract: Regulatory T cells (Tregs), including natural CD4+CD25+ Tregs and inducible IL-10 producing T regulatory type 1 (TR1) cells, maintain tolerance and inhibit autoimmunity. Recently, increased percentages of Tregs have been observed in the blood of septic patients, and ex vivo-activated Tregs were shown to prevent polymicrobial sepsis mortality. Whether endogenous Tregs contribute to sepsis outcome remains unclear. Polymicrobial sepsis, induced by cecal ligation and puncture, caused an increased number of splenic Tregs compared with sham-treated mice. Splenic CD4+CD25+ T cells from septic mice expressed higher levels of Foxp3 mRNA and were more efficient suppressors of CD4+CD25− T effector cell proliferation. Isolated CD4+ T cells from septic mice displayed increased intracellular IL-10 staining following stimulation, indicating that TR1 cells may also be elevated in sepsis. Surprisingly, Ab depletion of total CD4+ or CD4+CD25+ populations did not affect mortality. Furthermore, no difference in survival outcome was found between CD25 or IL-10 null mice and wild-type littermates, indicating that Treg or TR1-generated IL-10 are not required for survival. These results demonstrate that, although sepsis causes a relative increase in Treg number and increases their suppressive function, their presence does not contribute significantly to overall survival in this model.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.177.11.7943
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2006
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Structure-Based Selection of Small Molecules To Alter Allele-Specific MHC Class II Antigen Presentation
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 187, No. 11 ( 2011-12-01), p. 5921-5930
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 187, No. 11 ( 2011-12-01), p. 5921-5930
    Abstract: Class II major histocompatibility molecules are the primary susceptibility locus for many autoimmune disorders, including type 1 diabetes. Human DQ8 and I-Ag7, in the NOD mouse model of spontaneous autoimmune diabetes, confers diabetes risk by modulating presentation of specific islet peptides in the thymus and periphery. We used an in silico molecular docking program to screen a large “druglike” chemical library to define small molecules capable of occupying specific structural pockets along the I-Ag7 binding groove, with the objective of influencing presentation to T cells of the autoantigen insulin B chain peptide consisting of amino acids 9–23. In this study we show, using both murine and human cells, that small molecules can enhance or inhibit specific TCR signaling in the presence of cognate target peptides, based upon the structural pocket targeted. The influence of compounds on the TCR response was pocket dependent, with pocket 1 and 6 compounds inhibiting responses and molecules directed at pocket 9 enhancing responses to peptide. At nanomolar concentrations, the inhibitory molecules block the insulin B chain peptide consisting of amino acids 9–23, endogenous insulin, and islet-stimulated T cell responses. Glyphosine, a pocket 9 compound, enhances insulin peptide presentation to T cells at concentrations as low as 10 nM, upregulates IL-10 secretion, and prevents diabetes in NOD mice. These studies present a novel method for identifying small molecules capable of both stimulating and inhibiting T cell responses, with potentially therapeutic applications.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1100746
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
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  • 4
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    Genetic and Small Molecule Disruption of the AID/RAD51 Axis Similarly Protects Nonobese Diabetic Mice from Type 1 Diabetes through Expansion of Regulatory B Lymphocytes
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 11 ( 2017-06-01), p. 4255-4267
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 11 ( 2017-06-01), p. 4255-4267
    Abstract: B lymphocytes play a key role in type 1 diabetes (T1D) development by serving as a subset of APCs preferentially supporting the expansion of autoreactive pathogenic T cells. As a result of their pathogenic importance, B lymphocyte–targeted therapies have received considerable interest as potential T1D interventions. Unfortunately, the B lymphocyte–directed T1D interventions tested to date failed to halt β cell demise. IgG autoantibodies marking humans at future risk for T1D indicate that B lymphocytes producing them have undergone the affinity-maturation processes of class switch recombination and, possibly, somatic hypermutation. This study found that CRISPR/Cas9-mediated ablation of the activation-induced cytidine deaminase gene required for class switch recombination/somatic hypermutation induction inhibits T1D development in the NOD mouse model. The activation-induced cytidine deaminase protein induces genome-wide DNA breaks that, if not repaired through RAD51-mediated homologous recombination, result in B lymphocyte death. Treatment with the RAD51 inhibitor 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid also strongly inhibited T1D development in NOD mice. The genetic and small molecule–targeting approaches expanded CD73+ B lymphocytes that exert regulatory activity suppressing diabetogenic T cell responses. Hence, an initial CRISPR/Cas9-mediated genetic modification approach has identified the AID/RAD51 axis as a target for a potentially clinically translatable pharmacological approach that can block T1D development by converting B lymphocytes to a disease-inhibitory CD73+ regulatory state.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1700024
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
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  • 5
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    Systemic Overexpression of IL-10 Induces CD4+CD25+ Cell Populations In Vivo and Ameliorates Type 1 Diabetes in Nonobese Diabetic Mice in a Dose-Dependent Fashion
    The American Association of Immunologists ; 2003
    In:  The Journal of Immunology Vol. 171, No. 5 ( 2003-09-01), p. 2270-2278
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 171, No. 5 ( 2003-09-01), p. 2270-2278
    Abstract: Early systemic treatment of nonobese diabetic mice with high doses of recombinant adeno-associated virus (rAAV) vector expressing murine IL-10 prevents type 1 diabetes. To determine the therapeutic parameters and immunological mechanisms underlying this observation, female nonobese diabetic mice at 4, 8, and 12 wk of age were given a single i.m. injection of rAAV-murine IL-10 (104, 106, 108, and 109 infectious units (IU)), rAAV-vector expressing truncated murine IL-10 fragment (109 IU), or saline. Transduction with rAAV-IL-10 at 109 IU completely prevented diabetes in all animals injected at all time points, including, surprisingly, 12-wk-old animals. Treatment with 108 IU provided no protection in the 12-wk-old injected mice, partial prevention in 8-wk-old mice, and full protection in all animals injected at 4 wk of age. All other treatment groups developed diabetes at a similar rate. The rAAV-IL-10 therapy attenuated pancreatic insulitis, decreased MHC II expression on CD11b+ cells, increased the population of CD11b+ cells, and modulated insulin autoantibody production. Interestingly, rAAV-IL-10 therapy dramatically increased the percentage of CD4+CD25+ regulatory T cells. Adoptive transfer studies suggest that rAAV-IL-10 treatment alters the capacity of splenocytes to impart type 1 diabetes in recipient animals. This study indicates the potential for immunomodulatory gene therapy to prevent autoimmune diseases, including type 1 diabetes, and implicates IL-10 as a molecule capable of increasing the percentages of regulatory cells in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.171.5.2270
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2003
    detail.hit.zdb_id: 1475085-5
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  • 6
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    Online Resource
    Polyanion-Induced Self-Association of Complement Factor H
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 2 ( 2009-01-15), p. 1061-1068
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 2 ( 2009-01-15), p. 1061-1068
    Abstract: Factor H is the primary soluble regulator of activation of the alternative pathway of complement. It prevents activation of complement on host cells and tissues upon association with C3b and surface polyanions such as sialic acids, heparin, and other glycosaminoglycans. Here we show that interaction with polyanions causes self-association forming tetramers of the 155,000 Da glycosylated protein. Monomeric human factor H is an extended flexible protein that exhibits an apparent size of 330,000 Da, relative to globular standards, during gel filtration chromatography in the absence of polyanions. In the presence of dextran sulfate (5000 Da) or heparin an intermediate species of apparent m.w. 700,000 and a limit species of m.w. 1,400,000 were observed by gel filtration. Sedimentation equilibrium analysis by analytical ultracentrifugation indicated a monomer Mr of 163,000 in the absence of polyanions and a Mr of 607,000, corresponding to a tetramer, in the presence of less than a 2-fold molar excess of dextran sulfate. Increasing concentrations of dextran sulfate increased binding of factor H to zymosan-C3b 4.5-fold. This result was accompanied by an increase in both the decay accelerating and cofactor activity of factor H on these cells. An expressed fragment encompassing the C-terminal polyanion binding site (complement control protein domains 18–20) also exhibited polyanion-induced self-association, suggesting that the C-terminal ends of factor H mediate self-association. The results suggest that recognition of polyanionic markers on host cells and tissues by factor H, and the resulting regulation of complement activation, may involve formation of dimers and tetramers of factor H.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.182.2.1061
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
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  • 7
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    Insulin Receptor–Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice
    The American Association of Immunologists ; 2021
    In:  The Journal of Immunology Vol. 206, No. 7 ( 2021-04-01), p. 1443-1453
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 206, No. 7 ( 2021-04-01), p. 1443-1453
    Abstract: Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell–mediated autoimmune destruction of insulin-producing pancreatic β cells occurs. In previous work, when purified IR+ and IR− T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p & lt; 0.01) and controls (p & lt; 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p & lt; 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1900357
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2021
    detail.hit.zdb_id: 1475085-5
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  • 8
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    A Glutamic Acid Decarboxylase 65-Specific Th2 Cell Clone Immunoregulates Autoimmune Diabetes in Nonobese Diabetic Mice
    The American Association of Immunologists ; 2001
    In:  The Journal of Immunology Vol. 166, No. 11 ( 2001-06-01), p. 6925-6936
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 166, No. 11 ( 2001-06-01), p. 6925-6936
    Abstract: Several studies have provided indirect evidence in support of a role for β cell-specific Th2 cells in regulating insulin-dependent diabetes (IDDM). Whether a homogeneous population of Th2 cells having a defined β cell Ag specificity can prevent or suppress autoimmune diabetes is still unclear. In fact, recent studies have demonstrated that β cell-specific Th2 cell clones can induce IDDM. In this study we have established Th cell clones specific for glutamic acid decarboxylase 65 (GAD65), a known β cell autoantigen, from young unimmunized nonobese diabetic (NOD) mice. Adoptive transfer of a GAD65-specific Th2 cell clone (characterized by the secretion of IL-4, IL-5, and IL-10, but not IFN-γ or TGF-β) into 2- or 12-wk-old NOD female recipients prevented the progression of insulitis and subsequent development of overt IDDM. This prevention was marked by the establishment of a Th2-like cytokine profile in response to a panel of β cell autoantigens in cultures established from the spleen and pancreatic lymph nodes of recipient mice. The immunoregulatory function of a given Th cell clone was dependent on the relative levels of IFN-γ vs IL-4 and IL-10 secreted. These results provide direct evidence that β cell-specific Th2 cells can indeed prevent and suppress autoimmune diabetes in NOD mice.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.166.11.6925
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2001
    detail.hit.zdb_id: 1475085-5
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  • 9
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    Rabbit Polyclonal Mouse Antithymocyte Globulin Administration Alters Dendritic Cell Profile and Function in NOD Mice to Suppress Diabetogenic Responses
    The American Association of Immunologists ; 2009
    In:  The Journal of Immunology Vol. 182, No. 8 ( 2009-04-15), p. 4608-4615
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 182, No. 8 ( 2009-04-15), p. 4608-4615
    Abstract: Mouse antithymocyte globulin (mATG) prevents, as well as reverses, type 1 diabetes in NOD mice, through mechanisms involving modulation of the immunoregulatory activities of T lymphocytes. Dendritic cells (DC) play a pivotal role in the generation of T cell responses, including those relevant to the autoreactive T cells enabling type 1 diabetes. As Abs against DC are likely generated during production of mATG, we examined the impact of this preparation on the phenotype and function of DC to elucidate novel mechanisms underlying its beneficial activities. In vivo, mATG treatment transiently induced the trafficking of mature CD8− predominant DC into the pancreatic lymph node of NOD mice. Splenic DC from mATG-treated mice also exhibited a more mature phenotype characterized by reduced CD8 expression and increased IL-10 production. The resultant DC possessed a potent capacity to induce Th2 responses when cultured ex vivo with diabetogenic CD4+ T cells obtained from BDC2.5 TCR transgenic mice. Cotransfer of these Th2-deviated CD4+ T cells with splenic cells from newly diabetic NOD mice into NOD.RAG−/− mice significantly delayed the onset of diabetes. These studies suggest the alteration of DC profile and function by mATG may skew the Th1/Th2 balance in vivo and through such actions, represent an additional novel mechanism by which this agent provides its beneficial activities.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.0713269
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2009
    detail.hit.zdb_id: 1475085-5
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  • 10
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    Overexpression of the PTPN22 Autoimmune Risk Variant LYP-620W Fails to Restrain Human CD4+ T Cell Activation
    The American Association of Immunologists ; 2021
    In:  The Journal of Immunology Vol. 207, No. 3 ( 2021-08-01), p. 849-859
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 207, No. 3 ( 2021-08-01), p. 849-859
    Abstract: A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), which encodes lymphoid-tyrosine phosphatase (LYP), confers genetic risk for multiple autoimmune diseases including type 1 diabetes. LYP has been putatively demonstrated to attenuate proximal T and BCR signaling. However, limited data exist regarding PTPN22 expression within primary T cell subsets and the impact of the type 1 diabetes risk variant on human T cell activity. In this study, we demonstrate endogenous PTPN22 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- (p & lt; 0.05) and 3.6-fold (p & lt; 0.001) more PTPN22 transcripts in resting CD4+ memory and regulatory T cells (Tregs), respectively, over naive CD4+ T cells, with expression peaking 24 h postactivation. When LYP was overexpressed in conventional CD4+ T cells, TCR signaling and activation were blunted by LYP-620R (p & lt; 0.001) but only modestly affected by the LYP-620W risk variant versus mock-transfected control, with similar results observed in Tregs. LYP overexpression only impacted proliferation following activation by APCs but not anti-CD3– and anti-CD28–coated microbeads, suggesting LYP modulation of pathways other than TCR. Notably, proliferation was significantly lower with LYP-620R than with LYP-620W overexpression in conventional CD4+ T cells but was similar in Treg. These data indicate that the LYP-620W variant is hypomorphic in the context of human CD4+ T cell activation and may have important implications for therapies seeking to restore immunological tolerance in autoimmune disorders.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2000708
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2021
    detail.hit.zdb_id: 1475085-5
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