The Journal of Immunology (J Immunol)
The JI publishes novel results in all areas of experimental immunology.
- Impact factor5.79
- WebsiteThe Journal of Immunology website
Other titlesJournal of immunology (Baltimore, Md.: 1950: Online), The journal of immunology, JI
Material typeDocument, Internet resource
Document typeInternet Resource, Computer File, Journal / Magazine / Newspaper
Publications in this journal
Article: Comment on "Induced IL-17-Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β".The Journal of Immunology 06/2013; 190(12):5909-10.
Article: What is and what should always have been: long-lived plasma cells induced by T cell-independent antigens.[show abstract] [hide abstract]
ABSTRACT: It is well accepted that Ag-induced B cell differentiation often results in the generation of exceptionally long-lived plasma cells. Much of the work supporting this viewpoint stems from studies focused on germinal center-derived plasma cells secreting high-affinity isotype-switched Abs in mice immunized with T cell-dependent Ags. In contrast, less attention has been devoted to understanding Ab responses to T cell-independent Ags and pathogens. In this study, we review recent work showing that T cell-independent Ags consisting of either polysaccharides or LPSs also induce the formation of long-lived plasma cells, despite their general inability to sustain germinal center responses. This new information provides a framework for more fully understanding the forces underlying immunity to pathogens that resist T cell recognition and the extracellular cues governing plasma cell longevity.The Journal of Immunology 06/2013; 190(12):5913-8.
Article: Response to Comment on "Induced IL-17-Producing Invariant NKT Cells Require Activation in Presence of TGF-β and IL-1β".The Journal of Immunology 06/2013; 190(12):5910-1.
Article: Comment on "TLR9 Provokes Inflammation in Response to Fetal DNA: Mechanism for Fetal Loss in Preterm Birth and Preeclampsia".The Journal of Immunology 06/2013; 190(12):5909.
Article: Human Bocavirus VP2 Upregulates IFN-β Pathway by Inhibiting Ring Finger Protein 125–Mediated Ubiquitination of Retinoic Acid–Inducible Gene-I Huanle Luo, Zhenfeng Zhang, Zhenhua Zheng, Xianliang Ke, Xiaowei Zhang, Qian Li, Yan Liu, Bingke Bai, Panyong Mao, Qinxue Hu, and Hanzhong WangThe Journal of Immunology 06/2013;
Article: Combined Inhibition of Complement (C5) and CD14 Markedly Attenuates Inflammation, Thrombogenicity, and Hemodynamic Changes in Porcine Sepsis.[show abstract] [hide abstract]
ABSTRACT: Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine sepsis. In the present study, we explored the effect of the C5 and leukotriene B4 inhibitor Ornithodoros moubata complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory, hemostatic, and hemodynamic responses in porcine Escherichia coli-induced sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the terminal complement complex and significantly decreased leukotriene B4 levels in septic pigs. Granulocyte tissue factor expression, formation of thrombin-antithrombin complexes (p < 0.001), and formation of TNF-α and IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined therapy attenuated the formation of plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and IL-8, increased the formation of IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in sepsis as it efficiently attenuated inflammation and thrombogenicity and delayed hemodynamic changes.The Journal of Immunology 06/2013;
Article: B Cell-Intrinsic TLR7 Signaling Is Required for Optimal B Cell Responses during Chronic Viral Infection.[show abstract] [hide abstract]
ABSTRACT: The importance for activation of innate immunity by pattern recognition receptors in forming an effective adaptive immune response is well known. TLRs were demonstrated to be critical for Ab responses to a variety of immunizations. In particular, recent evidence suggests that B cell-intrinsic TLR signaling is required for optimal responses to virus-like Ags, but the mechanisms by which TLR signaling impacts Ab responses during infection in vivo is unclear. In the current study, we demonstrate that deficiency of TLR7 in B cells alone is sufficient to significantly impact Ab responses in mice during chronic viral infection. This effect was independent of T follicular helper cells and resulted in a loss of plasma cells generated later, but not early, in the response. The defect in plasma cell formation appeared to be secondary to a qualitative effect of TLR signaling on the germinal center (GC) B cell response. GC B cells in TLR7-deficient mice proliferated to a lesser extent and had a greater proportion of cells with phenotypic characteristics of light zone, relative to dark zone, GC B cells. These results suggest that B cell-intrinsic TLR signaling in vivo likely affects plasma cell output by altered selection of Ag-specific B cells in the GC.The Journal of Immunology 06/2013;
Article: STAT4 and T-bet Are Required for the Plasticity of IFN-γ Expression across Th2 Ontogeny and Influence Changes in Ifng Promoter DNA Methylation.[show abstract] [hide abstract]
ABSTRACT: CD4(+) T cells developing toward a Th2 fate express IL-4, IL-5, and IL-13 while inhibiting production of cytokines associated with other Th types, such as the Th1 cytokine IFN- γ. IL-4-producing Th2 effector cells give rise to a long-lived memory population committed to reactivation of the Th2 cytokine gene expression program. However, reactivation of these effector-derived cells under Th1-skewing conditions leads to production of IFN-γ along with IL-4 in the same cell. We now show that this flexibility ("plasticity") of cytokine expression is preceded by a loss of the repressive DNA methylation of the Ifng promoter acquired during Th2 polarization yet requires STAT4 along with T-box expressed in T cells. Surprisingly, loss of either STAT4 or T-box expressed in T cells increased Ifng promoter CpG methylation in both effector and memory Th2 cells. Taken together, our data suggest a model in which the expression of IFN-γ by Th2-derived memory cells involves attenuation of epigenetic repression in memory Th2 cells, combined with Th1-polarizing signals after their recall activation.The Journal of Immunology 06/2013;
Article: RKIP Contributes to IFN-γ Synthesis by CD8+ T Cells after Serial TCR Triggering in Systemic Inflammatory Response Syndrome.[show abstract] [hide abstract]
ABSTRACT: Systemic inflammatory response syndrome (SIRS) is associated with the development of severe medical complications, including progression to multiple organ dysfunction syndrome and even death. To date, only marginal improvements in terms of therapeutic options have been established for patients affected by SIRS. Raf kinase inhibitor protein (RKIP) is a regulator of MAPK and NF-κB signaling cascades, which are both critical for production of the proinflammatory cytokines responsible for SIRS initiation. By testing a T cell-dependent mouse model of SIRS that utilizes staphylococcal enterotoxin A specific for Vβ3(+) T cells, we show that RKIP is necessary for the exaggerated production of IFN-γ from SIRS splenocytes. This effect was not due to differences in T cell expansion, IL-10 production, or APC priming, but rather a cell-intrinsic defect lying downstream of the TCR in staphylococcal enterotoxin A-specific CD8(+) T cells. Importantly, mice lacking RKIP were still able to proliferate, survive, and contribute to cytokine production in response to pathogen associated molecular pattern-TLR-mediated stimuli, despite the TCR-dependent defects seen in our SIRS model. Finally, by blocking RKIP in wild-type SIRS splenocytes, the IFN-γ response by CD8(+) Vβ3(+) T cells was significantly diminished. These data suggest that RKIP may be a potential therapeutic target in SIRS by curbing effector cytokine production from CD8(+) T cells during serial TCR triggering.The Journal of Immunology 06/2013;
Article: CD160 Activation by Herpesvirus Entry Mediator Augments Inflammatory Cytokine Production and Cytolytic Function by NK Cells.[show abstract] [hide abstract]
ABSTRACT: Lymphocyte activation is regulated by costimulatory and inhibitory receptors, of which both B and T lymphocyte attenuator (BTLA) and CD160 engage herpesvirus entry mediator (HVEM). Notably, it remains unclear how HVEM functions with each of its ligands during immune responses. In this study, we show that HVEM specifically activates CD160 on effector NK cells challenged with virus-infected cells. Human CD56(dim) NK cells were costimulated specifically by HVEM but not by other receptors that share the HVEM ligands LIGHT, Lymphotoxin-α, or BTLA. HVEM enhanced human NK cell activation by type I IFN and IL-2, resulting in increased IFN-γ and TNF-α secretion, and tumor cell-expressed HVEM activated CD160 in a human NK cell line, causing rapid hyperphosphorylation of serine kinases ERK1/2 and AKT and enhanced cytolysis of target cells. In contrast, HVEM activation of BTLA reduced cytolysis of target cells. Together, our results demonstrate that HVEM functions as a regulator of immune function that activates NK cells via CD160 and limits lymphocyte-induced inflammation via association with BTLA.The Journal of Immunology 06/2013;
Article: Phl p 1-Specific Human Monoclonal IgE and Design of a Hypoallergenic Group 1 Grass Pollen Allergen Fragment.[show abstract] [hide abstract]
ABSTRACT: Detailed understanding of how Abs of the IgE isotype interact with allergen at the onset of an allergic reaction is of great importance for deciphering mechanisms involved in the development of disease and may aid in the design of hypoallergenic variants. In this study, we have used a set of human monoclonal IgE Abs derived from the repertoires of allergic individuals, specific for the major timothy grass pollen allergen Phl p 1, to gain detailed information on the interaction between Abs and allergen. These allergen-specific IgE are to varying degrees cross-reactive toward both different allergen isoforms and various group 1 allergens originating from other grass species. The usage of human monoclonal IgE, as an alternative to polyclonal preparations or mouse Abs, allowed us to locate several important IgE-binding epitopes on the C-terminal domain of Phl p 1, all clustered to an IgE-binding "hot spot." By introducing three mutations in the IgE-binding area of the C-terminal domain we were able to significantly reduce its reactivity with serum IgE. In conclusion, our study shows the great potential of using human monoclonal IgE as a tool for studies of the molecular interactions taking place during allergic responses. Furthermore, we present a novel IgE-hyporeactive fragment with the potential to be used as a safer hypoallergenic alternative in specific immunotherapy than the pollen extracts used today.The Journal of Immunology 06/2013;
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ABSTRACT: Preterm birth is the major cause of neonatal mortality and morbidity, and bacterial infections that ascend from the lower female reproductive tract are the most common route of uterine infection leading to preterm birth. The uterus and growing fetus are protected from ascending infection by the cervix, which controls and limits microbial access by the production of mucus, cytokines, and antimicrobial peptides. If this barrier is compromised, bacteria may enter the uterine cavity, leading to preterm birth. Using a mouse model, we demonstrate, to our knowledge for the first time, that viral infection of the cervix during pregnancy reduces the capacity of the female reproductive tract to prevent bacterial infection of the uterus. This is due to differences in susceptibility of the cervix to infection by virus during pregnancy and the associated changes in TLR and antimicrobial peptide expression and function. We suggest that preterm labor is a polymicrobial disease, which requires a multifactorial approach for its prevention and treatment.The Journal of Immunology 06/2013;
Article: Contrasting Effects of Anti-Ly49A Due to MHC Class I cis Binding on NK Cell-Mediated Allogeneic Bone Marrow Cell Resistance.[show abstract] [hide abstract]
ABSTRACT: NK subsets have activating and inhibitory receptors that bind MHC-I. Ly49A is a mouse inhibitory receptor that binds with high affinity to H2(d) in both a cis- and trans-manner. Ly49A cis-associations limit trans-interactions with H2(d)-expressing targets as well as mAb binding. We demonstrate that cis-interactions affect mAb effector functions. In vivo administration of anti-Ly49A depleted NK cells in H2(b) but not H2(d) mice. Despite lack of depletion, in vivo treatment with anti-Ly49A reduced NK killing capabilities and inhibited activation, partially due to its agonistic effect. These data explain the previously described in vivo effects on bone marrow allograft rejection observed with anti-Ly49A treatment in H2(d)-haplotype mice. However, prior treatment of mice with poly(I:C) or mouse CMV infection resulted in increased Ly49A expression and Ly49A(+) NK cell depletion in H2(d) mice. These data indicate that, although Ly49 mAbs can exert similar in vivo effects in mice with different MHC haplotypes, these effects are mediated via different mechanisms of action correlating with Ly49A expression levels and can be altered within the same strain contingent on stimuli. This illustrates the marked diversity of mAb effector functions due to the regulation of the level of expression of target Ags and responses by stimulatory incidents such as infection.The Journal of Immunology 06/2013;
Article: Neutrophil Recruitment to the Lung in Both C5a- and CXCL1-Induced Alveolitis Is Impaired in Vitamin D-Binding Protein-Deficient Mice.[show abstract] [hide abstract]
ABSTRACT: Knowledge of how neutrophils respond to chemotactic signals in a complex inflammatory environment is not completely understood. Moreover, even less is known about factors in physiological fluids that regulate the activity of chemoattractants. The vitamin D-binding protein (DBP) has been shown to significantly enhance chemotaxis to complement activation peptide C5a using purified proteins in vitro, and by ex vivo depletion of DBP in physiological fluids, but this function has not been determined in vivo. DBP null ((-/-)) mice were used to investigate how a systemic absence of this plasma protein affects leukocyte recruitment in alveolitis models of lung inflammation. DBP(-/-) mice had significantly reduced (∼50%) neutrophil recruitment to the lungs compared with their wild-type DBP(+/+) counterparts in three different alveolitis models, two acute and one chronic. The histology of DBP(-/-) mouse lungs also showed significantly less injury than wild-type animals. The chemotactic cofactor function of DBP appears to be selective for neutrophil recruitment, but, in contrast to previous in vitro results, in vivo DBP can enhance the activity of other chemoattractants, including CXCL1. The reduced neutrophil response in DBP(-/-) mice could be rescued to wild-type levels by administering exogenous DBP. Finally, in inflammatory fluids, DBP binds to G-actin released from damaged cells, and this complex may be the active chemotactic cofactor. To our knowledge, results show for the first time that DBP is a significant chemotactic cofactor in vivo and not specific for C5a, suggesting that this ubiquitous plasma protein may have a more significant role in neutrophil recruitment than previously recognized.The Journal of Immunology 06/2013;
Article: Different Modulation of Ptpn22 in Effector and Regulatory T Cells Leads to Attenuation of Autoimmune Diabetes in Transgenic Nonobese Diabetic Mice.[show abstract] [hide abstract]
ABSTRACT: Ptpn22 encodes PEST domain-enriched tyrosine phosphatase (Pep), which negatively regulates TCR proximal signaling and is strongly associated with a variety of autoimmune diseases in humans. The net effect of Pep on the balance of immunity and tolerance is uncertain because of the simultaneous inhibition of TCR-mediated signaling of effector and regulatory T cells (Tregs). In this study, we generated transgenic NOD mice that overexpressed Pep in T cells. The transgenic mice had a significantly lower incidence of spontaneous autoimmune diabetes, which was accompanied by fewer IFN-γ-producing T cells, and an increased ratio of CD4(+)Foxp3(+) Tregs to CD4(+)IFN-γ(+) or to CD8(+)IFN-γ(+) T cells, respectively, in pancreatic islets. Transgenic T cells showed markedly decreased TCR-mediated effector cell responses such as proliferation and Th1 differentiation. By contrast, the inhibitory effect of transgenic Pep on TCR signaling did not affect the differentiation of Tregs or their suppressive activity. Adoptive transfer experiments showed that transgenic splenocytes exhibited attenuated diabetogenic ability. To examine further the pathogenic features of transgenic T cells, we generated Ptpn22/BDC2.5 doubly transgenic mice and found reduced proliferation and Th1 differentiation in CD4(+) T lymphocytes with additional Pep in pancreatic lymph nodes but not in inguinal lymph nodes of NOD/SCID recipients. This finding indicates that transgenic Pep attenuates T cell functions in an islet Ag-driven manner. Taken together, our results demonstrate that Pep overexpression in T cells attenuates autoimmune diabetes in NOD mice by preferentially modulating TCR signaling-mediated functions in diabetogenic T cells but not in Tregs.The Journal of Immunology 06/2013;
Article: Notch-Regulated Periphery B Cell Differentiation Involves Suppression of E Protein Function.[show abstract] [hide abstract]
ABSTRACT: Notch signaling pathway plays important roles in promoting the generation of marginal zone (MZ) B cells at the expense of follicular (FO) B cells during periphery B cell maturation, but the underlying molecular mechanisms are not well understood. We hypothesize that Notch favors the generation of MZ B cells by downregulating E protein activity. In this study, we demonstrated that expression of Id2 and ankyrin-repeat SOCS box-containing protein 2 was elevated in MZ B cells and by Notch signaling. Id2 inhibits the DNA binding activity of E proteins, whereas ankyrin-repeat SOCS box-containing protein 2 facilitates E protein ubiquitination. Next, we examined the phenotypes of splenic B cells in mice expressing constitutively active Notch1 and/or two gain-of-function mutants of E proteins that counteract Id2-mediated inhibition or Notch-induced degradation. We found that upregulation of E proteins promoted the formation of FO B cells, whereas it suppressed the maturation of MZ B cells. In contrast, excessive amounts of Notch1 stimulated the differentiation of MZ B cells and inhibited the production of FO B cells. More interestingly, the effects of Notch1 were reversed by gain of E protein function. Furthermore, high levels of Bcl-6 expression in FO B cells was shown to be diminished by Notch signaling and restored by E proteins. In addition, E proteins facilitated and Notch hindered the differentiation of transitional B cells. Taken together, it appears that Notch regulates peripheral B cell differentiation, at least in part, through opposing E protein function.The Journal of Immunology 06/2013;
Article: Control of T Cell Fates and Immune Tolerance by p38α Signaling in Mucosal CD103+ Dendritic Cells.[show abstract] [hide abstract]
ABSTRACT: Dendritic cells (DCs) play a crucial role in launching protective adaptive immunity against pathogens while maintaining immune tolerance to self-Ags. However, how intracellular signaling pathways program DCs to mediate tolerogenic responses remains largely unexplored. In this study, we describe that p38α signaling in CD103(+) mesenteric lymph node DCs reciprocally regulates the differentiation of anti-inflammatory induced regulatory T cells and proinflammatory Th1 cells from naive precursors and promotes mucosal tolerance. Deficiency of p38α in CD103(+) DCs inhibited the generation of induced regulatory T cells while promoting Th1 cell development in a TGF-β2-dependent manner. Consequently, loss of p38α in DCs prevented induction of oral tolerance in vivo. Moreover, p38α in CD103(+) DCs was required for optimal expression of retinaldehyde dehydrogenase, a key enzyme for retinoic acid synthesis, which in turn imprinted gut-homing receptors on responding T cells. Consistent with a crucial role of p38α to program the tolerogenic activity of CD103(+) DCs, such DC subset contained constitutive activity of p38α and abundant expression of TGF-β2 and retinaldehyde dehydrogenase. Our studies identify a key mechanism of DC-mediated coupling of T cell differentiation and trafficking that orchestrates mucosal immune tolerance.The Journal of Immunology 06/2013;
Article: Microenvironments in Tuberculous Granulomas Are Delineated by Distinct Populations of Macrophage Subsets and Expression of Nitric Oxide Synthase and Arginase Isoforms.[show abstract] [hide abstract]
ABSTRACT: Macrophages in granulomas are both antimycobacterial effector and host cell for Mycobacterium tuberculosis, yet basic aspects of macrophage diversity and function within the complex structures of granulomas remain poorly understood. To address this, we examined myeloid cell phenotypes and expression of enzymes correlated with host defense in macaque and human granulomas. Macaque granulomas had upregulated inducible and endothelial NO synthase (iNOS and eNOS) and arginase (Arg1 and Arg2) expression and enzyme activity compared with nongranulomatous tissue. Immunohistochemical analysis indicated macrophages adjacent to uninvolved normal tissue were more likely to express CD163, whereas epithelioid macrophages in regions where bacteria reside strongly expressed CD11c, CD68, and HAM56. Calprotectin-positive neutrophils were abundant in regions adjacent to caseum. iNOS, eNOS, Arg1, and Arg2 proteins were identified in macrophages and localized similarly in granulomas across species, with greater eNOS expression and ratio of iNOS/Arg1 expression in epithelioid macrophages as compared with cells in the lymphocyte cuff. iNOS, Arg1, and Arg2 expression in neutrophils was also identified. The combination of phenotypic and functional markers support that macrophages with anti-inflammatory phenotypes localized to outer regions of granulomas, whereas the inner regions were more likely to contain macrophages with proinflammatory, presumably bactericidal, phenotypes. Together, these data support the concept that granulomas have organized microenvironments that balance antimicrobial anti-inflammatory responses to limit pathology in the lungs.The Journal of Immunology 06/2013;
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ABSTRACT: Class I HLAs generally present peptides of 8-10 aa in length, although it is unclear whether peptide length preferences are affected by HLA polymorphism. In this study, we investigated the CD8(+) T cell response to the BZLF1 Ag of EBV, which includes overlapping sequences of different size that nevertheless conform to the binding motif of the large and abundant HLA-B*44 supertype. Whereas HLA-B*18:01(+) individuals responded strongly and exclusively to the octamer peptide (173)SELEIKRY(180), HLA-B*44:03(+) individuals responded to the atypically large dodecamer peptide (169)EECDSELEIKRY(180), which encompasses the octamer peptide. Moreover, the octamer peptide bound more stably to HLA-B*18:01 than did the dodecamer peptide, whereas, conversely, HLA-B*44:03 bound only the longer peptide. Furthermore, crystal structures of these viral peptide-HLA complexes showed that the Ag-binding cleft of HLA-B*18:01 was more ideally suited to bind shorter peptides, whereas HLA-B*44:03 exhibited characteristics that favored the presentation of longer peptides. Mass spectrometric identification of > 1000 naturally presented ligands revealed that HLA-B*18:01 was more biased toward presenting shorter peptides than was HLA-B*44:03. Collectively, these data highlight a mechanism through which polymorphism within an HLA class I supertype can diversify determinant selection and immune responses by varying peptide length preferences.The Journal of Immunology 06/2013;
Article: T Cell Activation Threshold Regulated by E3 Ubiquitin Ligase Cbl-b Determines Fate of Inducible Regulatory T Cells.[show abstract] [hide abstract]
ABSTRACT: E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-b (Cbl-b) is critical for establishing the threshold for T cell activation and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of CD4(+)CD25(+) inducible regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naive CD4(+)CD25(-) T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is downregulated in vitro. Using TCR-transgenic Rag(-/-) mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation.The Journal of Immunology 06/2013;
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
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