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  • The American Association of Immunologists  (26)
  • 1
    Online Resource
    Online Resource
    The Polyanionic Drug Suramin Neutralizes Histones and Prevents Endotheliopathy
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 211, No. 4 ( 2023-08-15), p. 648-657
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 211, No. 4 ( 2023-08-15), p. 648-657
    Abstract: Drugs are needed to protect against the neutrophil-derived histones responsible for endothelial injury in acute inflammatory conditions such as trauma and sepsis. Heparin and other polyanions can neutralize histones but challenges with dosing or side effects such as bleeding limit clinical application. In this study, we demonstrate that suramin, a widely available polyanionic drug, completely neutralizes the toxic effects of individual histones, but not citrullinated histones from neutrophil extracellular traps. The sulfate groups on suramin form stable electrostatic interactions with hydrogen bonds in the histone octamer with a dissociation constant of 250 nM. In cultured endothelial cells (Ea.Hy926), histone-induced thrombin generation was significantly decreased by suramin. In isolated murine blood vessels, suramin abolished aberrant endothelial cell calcium signals and rescued impaired endothelial-dependent vasodilation caused by histones. Suramin significantly decreased pulmonary endothelial cell ICAM-1 expression and neutrophil recruitment caused by infusion of sublethal doses of histones in vivo. Suramin also prevented histone-induced lung endothelial cell cytotoxicity in vitro and lung edema, intra-alveolar hemorrhage, and mortality in mice receiving a lethal dose of histones. Protection of vascular endothelial function from histone-induced damage is a novel mechanism of action for suramin with therapeutic implications for conditions characterized by elevated histone levels.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200703
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Exacerbated Susceptibility to Infection-Stimulated Immunopathology in CD1d-Deficient Mice
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 174, No. 12 ( 2005-06-15), p. 7904-7911
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 174, No. 12 ( 2005-06-15), p. 7904-7911
    Abstract: Mice lacking functional CD1d genes were used to study mechanisms of resistance to the protozoan parasite Toxoplasma gondii. Wild-type (WT) BALB/c mice, CD1d-deficient BALB/c mice, and WT C57BL/6 mice all survived an acute oral infection with a low dose of mildly virulent strain ME49 T. gondii cysts. In contrast, most CD1d-deficient C57BL/6 mice died within 2 wk of infection. Despite having parasite burdens that were only slightly higher than WT mice, CD1d-deficient C57BL/6 mice displayed greater weight loss and intestinal pathology. In C57BL/6 mice, CD4+ cells can cause intestinal pathology during T. gondii infection. Compared with WT mice, infected CD1d-deficient C57BL/6 mice had higher frequencies and numbers of activated (CD44high) CD4+ cells in mesenteric lymph nodes. Depletion of CD4+ cells from CD1d-deficient mice reduced weight loss and prolonged survival, demonstrating a functional role for CD4+ cells in their increased susceptibility to T. gondii infection. CD1d-deficient mice are deficient in Vα14+ T cells, a major population of NKT cells. Involvement of these cells in resistance to T. gondii was investigated using gene-targeted Jα18-deficient C57BL/6 mice, which are deficient in Vα14+ T cells. These mice did not succumb to acute infection, but experienced greater weight loss and more deaths than B6 mice during chronic infection, indicating that Vα14+ cells contribute to resistance to T. gondii. The data identify CD4+ cells as a significant component of the marked susceptibility to T. gondii infection observed in CD1d-deficient C57BL/6mice, and establish T. gondii as a valuable tool for deciphering CD1d-dependent protective mechanisms.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.174.12.7904
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Online Resource
    Polymorphisms in the CD1d Promoter That Regulate CD1d Gene Expression Are Associated with Impaired NKT Cell Development
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 192, No. 1 ( 2014-01-01), p. 189-199
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 1 ( 2014-01-01), p. 189-199
    Abstract: CD1d-restricted NKT cells comprise an innate-like T cell population that exerts significant influence over early events in the developing immune response. The frequency of NKT cells is highly variable in humans and in mice, but the basis for this variability remains unclear. In this study, we report a striking deficiency of type I NKT cells in the wild-derived inbred strains PWD/PhJ, SPRET/EiJ, and CAST/EiJ. Investigation of the underlying basis for the lack of type I NKT cells revealed that one strain, PWD/PhJ, exhibited a significant impairment in thymocyte and splenocyte CD1d gene and protein expression. Accordingly, both thymocytes and bone marrow–derived dendritic cells from PWD mice exhibited a significant impairment in the ability to present α-galactosylceramide to NKT cells. The impaired PWD CD1d gene expression was due to impaired CD1d promoter activity. Fine-mapping of the promoter activity revealed that two single nucleotide substitutions at positions −331 and −164 in the proximal promoter were each sufficient to account for the diminished PWD CD1d promoter activity. Examination of the strain distribution pattern of these polymorphisms revealed that, of 19 strains analyzed, only PWD and PWK mice possessed both CD1d promoter polymorphisms. A subsequent examination of the PWK strain revealed that it also exhibited impaired thymocyte CD1d expression and very low numbers of NKT cells. Taken together, these results provide new insight into the control of CD1d gene expression, and they have implications for the evolution of CD1d and type I NKT cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1301451
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Online Resource
    Slamf6 acts as a negative regulator of NKT cell expansion in the presence of a strong agonist
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 133.20-133.20
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 133.20-133.20
    Abstract: Signaling lymphocyte activation marker family member 6 (Slamf6) is a cell surface signaling receptor that plays an important role in NKT cell development. Upon activation with the CD1d ligand α-galactosylceramide (αGalCer), NKT cell Slamf6 expression increases dramatically (~10-fold) and it maintains this high level of expression for at least 5 days after activation. The mechanisms through which Slamf6 regulates NKT cell function are largely unknown. To investigate the effect of Slamf6 on peripheral NKT cell populations, we challenged C57BL/6 (B6) or B6.Slamf6−/− mice with the NKT-specific agonist αGalCer. Examination of liver NKT cell numbers 3 days after challenge revealed a 50-fold increase in B6 mice over vehicle-treated controls. In contrast, we observed a 270-fold increase in NKT cells in B6.Slamf6−/− mice versus controls. An analysis of spleen NKT cells yielded similar results. A comparison of in vivo BrdU uptake by NKT cells between B6 and B6.Slamf6−/− mice revealed no significant differences in proliferation. In addition, NKT cell intracellular IFN-γ, IL-4, and TNF production between B6 and B6.Slamf6−/− mice after administration of αGalCer revealed no difference in the production of these cytokines. We next evaluated the Slamf6-specific effect on NKT cell expansion using an in vitro co-culture system. Cross-linking of Slamf6 on purified B6 NKT cells resulted in diminished NKT cell expansion and increased numbers of TUNEL+ NKT cells. Taken together, these data support a model where Slamf6 acts as a negative regulator of NKT cell expansion in the presence of a strong agonist by regulating the death threshold of NKT cells. These data suggest that Slamf6 blockade could be a useful tool to manipulate the expansion of NKT cells in vivo.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.196.Supp.133.20
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Influence of SLAM/SAP signaling on γδ T cell TCR signal strength during thymic development
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 219.17-219.17
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 219.17-219.17
    Abstract: Innate-like T cells are unusual T cells that are enriched in mucosal tissues, where they constitute a prominent source of pro-inflammatory cytokines like IL-17 and IFN-γ. During thymic development, mouse γδ T cells commit to either γδT1, γδT2, or γδT17 phenotypes through mechanisms that remain unclear. Recent observations from our laboratory have suggested a role for the SLAM/SAP signaling pathway in γδ T cell thymic developmental programming. Here, we investigated the influence of the SLAM/SAP signaling pathway on γδ TCR signal strength during thymic development. Using Nur77 GFPexpression as a readout of TCR signal strength, we observed significantly greater Nur77 GFPexpression in B6.Nur77 GFP.SAP −/−thymic γδ T cells compared their B6.Nur77 GFPcounterparts, suggesting that SAP inhibited TCR signal strength. Consistent with these findings, we observed significantly greater Erk phosphorylation in CD3-stimulated B6.SAP −/−thymic γδ T cells. In vitrostimulation of thymic γδ T cells with anti-TCRδ and anti-SLAM family receptors revealed that SLAMF6 co-stimulation resulted in decreased Erk phosphorylation, but increased Nur77 GFPexpression. Surprisingly, the effects of SLAMF6 co-stimulation on γδ TCR signaling were SAP-independent. Together, these data suggest an inhibitory role for SAP in γδ TCR signaling during thymic developmental programming.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.219.17
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 6
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    Online Resource
    Sex-specific regulation of CNS autoimmunity by the signal lymphocytic activation molecule ( Slam ) locus
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 55.25-55.25
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 55.25-55.25
    Abstract: Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS). Epidemiological studies have documented a 3–6 fold increase in MS incidence and prevalence in females over the last half-century, while remaining relatively stable in males. This establishes that gene×environment×sex interactions contribute to MS susceptibility. Genome-wide association studies (GWAS) of MS patients identified multiple candidate genes, including a locus containing the signal lymphocytic activation molecule (SLAM) family of receptors, a region rich in immune-relevant genes that is highly conserved between humans and mice. There are two major Slam haplotypes segregating in laboratory mice. Slam haplotype-1 is present in C57BL/6 (B6) mice and haplotype-2 is expressed in most other common inbred laboratory strains, including 129 mice. The congenic B6.129c1 mouse possesses the 129-derived Slam haplotype-2 locus on the B6 background, which allows for assessing the potential contribution of SLAM family genes to MS susceptibility using the myelin oligodendrocyte (MOG) model of experimental autoimmune encephalomyelitis (EAE). We show that male B6.129c1 congenic mice demonstrate significant protection against MOG-EAE, but only in males. Furthermore, draining lymph nodes from immunized B6.129c1 males, but not females, had increased Foxp3+ regulatory T cells (Treg) and IL-10 levels compared with B6, suggesting that SLAM/Slam haplotypes regulate autoimmunity by modulating the generation of immunoregulatory cells in a sex-specific manner. Taken together, our results support a role for the SLAM locus is MS pathogenesis, and reveal a novel sexual dimorphism in the genetic control of this autoimmune disease
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.55.25
    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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  • 7
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    Online Resource
    Single-cell TCR analysis of mouse lung V γ 4 γδ T cells reveals a link between TCR clonotypes, SLAM family receptor expression, and effector function
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 148.14-148.14
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 148.14-148.14
    Abstract: γδ T cells are unusual T cells that are highly enriched in mucosal tissues where they constitute a prominent source of pro-inflammatory cytokines like IL-17 and IFN-γ. The TCR usage of tissue-specific γδ T cells is often associated with specific effector functions. We have recently found that IL-17- and IFN-γ-producing Vγ4 γδ T cells in the mouse lung are marked by the expression of SLAMF1 and SLAMF6 receptors, respectively. The objective of this study was to investigate a possible link between SLAM-associated effector function and γδ TCR usage. We first identified the major Vγ4 γδ TCR clonotypes in the mouse lung (n=13 mice). Vγ4 γδ T cells were single cell-sorted and paired TCR clonotypes were identified using next-gen sequencing of TCR amplicon libraries. The data revealed that TRDV5, TRDV2, and TRDV7 chains accounted for 51.18%, 29.61%, and 14.96% of the productive TCRδ chain rearrangements, respectively. While TRDV5 and TRDV2 CDR3 sequences were limited in diversity, TRDV7 CDR3 sequences were highly diverse. A significant fraction (30.46%) of the TRDV5 sequences were characterized by an invariant germline-encoded Vδ5Dδ2Jδ1 sequence. A comparison between sorted SLAMF1+ and SLAMF6+lung Vγ4 γδ T cells revealed that TRDV5 and TRDV2 chains were predominantly associated with SLAMF1+IL-17+ γδ T cells while the TRDV7 chain was predominantly associated with SLAMF6+IFN-γ+ γδ T cells. Moreover, the invariant germline-encoded TRDV5 sequence was primarily associated with SLAMF1+IL-17+ cells. These data indicate that the lung Vγ4 γδ TCR repertoire is limited in diversity and that specific lung Vγ4 γδ TCR clonotypes segregate with the expression of discrete SLAM family receptors.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.148.14
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 8
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    Online Resource
    Cellular immunity patterns of rDEN2Δ30 (Tonga/74) support its suitability as a human DENV challenge strain.
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 1_Supplement ( 2017-05-01), p. 199.12-199.12
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 1_Supplement ( 2017-05-01), p. 199.12-199.12
    Abstract: The need for human DENV challenge model to better evaluate DENV candidate vaccines has become of extreme importance in the past years after neutralizing antibody failure to be a good correlate of protection and the lack of valid alternatives. rDEN2Δ30, a variant of DENV2 Tonga/74 strain lacking 30 nucleotides from its 3′ untranslated region, has been established as DENV human challenge model. In this study, DENV cellular immune responses of rDEN2Δ30 strain have been compared with natural infection to derive correlates of protection for DENV vaccines based on cellular immunity. For this purpose, HLA class I and class II restricted peptides have been predicted and tested in an IFN-gamma ELISPOT assay, to assess CD8+ and CD4+ T cell responses in healthy donors infected with rDEN2Δ30. CD8 and CD4 responses were detected in approximately 80% and 90% of donors respectively. Strong CD8 responses are detected in rDEN2Δ30 recipients and when compared with natural infections similarity in terms of magnitude and numbers of recognized epitopes is observed. In particular, the immunodominance hierarchy of the DENV nonstructural proteins NS3, NS5 is maintained in both analyzed cohorts. On the contrary, CD4 responses were mainly focused on nonstructural proteins and less strong respect to natural infection. Large overlap is observed in the epitopes recognized by rDEN2Δ30 infection and natural infection both for CD8 (100%) and CD4 (85%) responses. Finally, when rDEN2Δ30 CD8 response is compared with the one induced by other attenuated DENV isolates, a stronger response is observed. In conclusion, T cell response of rDENV2D30 has very similar specificity to natural infection supporting its suitability as an appropriate human DENV challenge model.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.198.Supp.199.12
    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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  • 9
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    Online Resource
    Single-cell proteogenomics reveals that SLAM/SAP signaling regulates the development of innate-like γδT cell subsets with distinct TCR repertoires
    The American Association of Immunologists ; 2021
    In:  The Journal of Immunology Vol. 206, No. 1_Supplement ( 2021-05-01), p. 14.09-14.09
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 206, No. 1_Supplement ( 2021-05-01), p. 14.09-14.09
    Abstract: Innate-like T cells are unusual T cells that are enriched in mucosal tissues, and which constitute a prominent source of pro-inflammatory cytokines like IL-17 and IFN-γ. While it is known that SLAM/SAP signaling is required for the development of innate-like iNKT and MAIT αβ T cells, far less is known about the role of this pathway in the development and function of γδ T cells. Here, we utilized a single-cell proteogenomics approach coupled with γδ V(D)J profiling to define the transcriptional landscape and developmental checkpoints of SAP-dependent γδ T cells. We found that SAP-dependent γδNKT TCRs utilized TRGV1 paired with TRAV15N-1 or TRAV15-1/DV6-1, and we identified two distinct developmental γδNKT stages in the neonatal thymus that were distinguished by SLAMF6 and SLAMF7 expression. Moreover, we found that a significant fraction of SLAMf1+innate-like γδT17 cells utilized TRGV4 and TRGV6, γ-chains paired with TRDV2 or TRDV5 δ-chains of limited diversity. Examination of SAP-deficient neonatal thymus revealed decreased numbers of mature SLAMF1+ γδT17 cells, which was associated with lower numbers of an invariant germline-encoded TRGV4/TRDV5 clonotype. Accordingly, we observed significant alterations in the SLAMF1+ γδT17 TCR repertoire in adult lung. We found that lung γδTIFN were CD44+CD45RB+CD27+ cells that co-expressed SLAMF6and SLAMF7, and that these cells predominantly utilized a diverse TRDV7 paired with TRGV4. Interestingly, we observed a specific decrease of these TRDV7+ γδTIFN cells in SAP-deficient mice, which we confirmed using qPCR. Altogether, these data indicate a crucial link between SLAM/SAP signaling and the development of functionally distinct innate-like γδ TCR clonotypes.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.206.Supp.14.09
    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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  • 10
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    Online Resource
    Serum Amyloid A Activates the NLRP3 Inflammasome and Promotes Th17 Allergic Asthma in Mice
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 187, No. 1 ( 2011-07-01), p. 64-73
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 187, No. 1 ( 2011-07-01), p. 64-73
    Abstract: IL-1β is a cytokine critical to several inflammatory diseases in which pathogenic Th17 responses are implicated. Activation of the NLRP3 inflammasome by microbial and environmental stimuli can enable the caspase-1–dependent processing and secretion of IL-1β. The acute-phase protein serum amyloid A (SAA) is highly induced during inflammatory responses, wherein it participates in systemic modulation of innate and adaptive immune responses. Elevated levels of IL-1β, SAA, and IL-17 are present in subjects with severe allergic asthma, yet the mechanistic relationship among these mediators has yet to be identified. In this study, we demonstrate that Saa3 is expressed in the lungs of mice exposed to several mixed Th2/Th17-polarizing allergic sensitization regimens. SAA instillation into the lungs elicits robust TLR2-, MyD88-, and IL-1–dependent pulmonary neutrophilic inflammation. Furthermore, SAA drives production of IL-1α, IL-1β, IL-6, IL-23, and PGE2, causes dendritic cell (DC) maturation, and requires TLR2, MyD88, and the NLRP3 inflammasome for secretion of IL-1β by DCs and macrophages. CD4+ T cells polyclonally stimulated in the presence of conditioned media from SAA-exposed DCs produced IL-17, and the capacity of polyclonally stimulated splenocytes to secrete IL-17 is dependent upon IL-1, TLR2, and the NLRP3 inflammasome. Additionally, in a model of allergic airway inflammation, administration of SAA to the lungs functions as an adjuvant to sensitize mice to inhaled OVA, resulting in leukocyte influx after Ag challenge and a predominance of IL-17 production from restimulated splenocytes that is dependent upon IL-1R signaling.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1100500
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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