Innate Immune Responses and Gut Microbiomes Distinguish HIV-Exposed from HIV-Unexposed Children in a Population-Specific Manner.
Smolen KK Abstract In both high- and low-income countries, HIV-negative children born to HIV-positive mothers (HIV exposed, uninfected [HEU]) are more susceptible to severe infection than HIV-unexposed, uninfected (HUU) children, with altered innate immunity hypothesized to be a cause. Both the gut microbiome and systemic innate immunity differ across biogeographically distinct settings, and the two are known to influence each other. And although the gut microbiome is influenced by HIV infection and may contribute to altered immunity, the biogeography of immune-microbiome correlations among HEU children have not ...
Source: Journal of Immunology - October 16, 2020 Category: Allergy & Immunology Authors: Amenyogbe N, Dimitriu P, Cho P, Ruck C, Fortuno ES, Cai B, Alimenti A, Côté HCF, Maan EJ, Slogrove AL, Esser M, Marchant A, Goetghebuer T, Shannon CP, Tebbutt SJ, Kollmann TR, Mohn WW, Smolen KK Tags: J Immunol Source Type: research

Polyglutamine-Related Aggregates Can Serve as a Potent Antigen Source for Cross-Presentation by Dendritic Cells.
In this study, we address this issue using a combination of in vitro (C57BL/6-derived mouse cell lines) and in vivo (C57BL/6 mouse strains) approaches involving stable and unstable versions of OVA model Ags displaying defective ribosomal protein-dependent and -independent Ag presentation, respectively. Apoptosis, but not necrosis, of donor cells was found associated with robust global protein aggregate formation and captured stable proteins permissive for cross-presentation. Potency of aggregates to serve as Ag source was directly demonstrated using polyglutamine-equipped model substrates. Collectively, our data implicate ...
Source: Journal of Immunology - October 16, 2020 Category: Allergy & Immunology Authors: Tabachnick-Cherny S, Pinto S, Berko D, Curato C, Wolf Y, Porat Z, Karmona R, Tirosh B, Jung S, Navon A Tags: J Immunol Source Type: research

Effect of Ibrutinib on the IFN Response of Chronic Lymphocytic Leukemia Cells.
Abstract The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has profound activity in chronic lymphocytic leukemia (CLL) but limited curative potential by itself. Residual signaling pathways that maintain survival of CLL cells might be targeted to improve ibrutinib's therapeutic activity, but the nature of these pathways is unclear. Ongoing activation of IFN receptors in patients on ibrutinib was suggested by the presence of type I and II IFN in blood together with the cycling behavior of IFN-stimulated gene (ISG) products when IFN signaling was blocked intermittently with the JAK inhibitor ruxolitinib. IFN sig...
Source: Journal of Immunology - October 16, 2020 Category: Allergy & Immunology Authors: Xia M, Luo TY, Shi Y, Wang G, Tsui H, Harari D, Spaner DE Tags: J Immunol Source Type: research

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Authors: PMID: 33020187 [PubMed - in process] (Source: Journal of Immunology)
Source: Journal of Immunology - October 8, 2020 Category: Allergy & Immunology Tags: J Immunol Source Type: research

IFN Regulatory Factor 3 in Health and Disease.
Abstract Immunity to viruses requires an array of critical cellular proteins that include IFN regulatory factor 3 (IRF3). Consequently, most viruses that infect vertebrates encode proteins that interfere with IRF3 activation. This review describes the cellular pathways linked to IRF3 activation and where those pathways are targeted by human viral pathogens. Moreover, key regulatory pathways that control IRF3 are discussed. Besides viral infections, IRF3 is also involved in resistance to some bacterial infections, in anticancer immunity, and in anticancer therapies involving DNA damage agents. A recent finding show...
Source: Journal of Immunology - October 8, 2020 Category: Allergy & Immunology Authors: Petro TM Tags: J Immunol Source Type: research

Peptide Binding to HLA-E Molecules in Humans, Nonhuman Primates, and Mice Reveals Unique Binding Peptides but Remarkably Conserved Anchor Residues.
Abstract Ag presentation via the nonclassical MHC class Ib molecule HLA-E, with nearly complete identity between the two alleles expressed in humans, HLA-E*01:01 and HLA-E*01:03, can lead to the activation of unconventional T cells in humans. Despite this virtual genetic monomorphism, differences in peptide repertoires binding to the two allelic variants have been reported. To further dissect and compare peptide binding to HLA-E*01:01 and HLA-E*01:03, we used an UV-mediated peptide exchange binding assay and an HPLC-based competition binding assay. In addition, we investigated binding of these same peptides to Mam...
Source: Journal of Immunology - October 4, 2020 Category: Allergy & Immunology Authors: Ruibal P, Franken KLMC, van Meijgaarden KE, van Loon JJF, van der Steen D, Heemskerk MHM, Ottenhoff THM, Joosten SA Tags: J Immunol Source Type: research

Intratumoral Activation of 41BB Costimulatory Signals Enhances CD8 T Cell Expansion and Modulates Tumor-Infiltrating Myeloid Cells.
In this study, we describe that the intratumoral administration of 41BB agonistic Abs led to increases in CD8 T cell infiltration followed by tumor regression in murine models. We found that granulocytes and monocytes rapidly replaced macrophages and dendritic cells in tumors following administration of anti-41BB Abs. Overall, myeloid cells from anti-41BB-treated tumors had an improved capacity to stimulate T cells in comparison with control-treated tumors. In human coculture systems, we demonstrated that the agonism of the 41BB-41BBL axis enhanced costimulatory signals and effector functions among APC and autologous TILs....
Source: Journal of Immunology - October 4, 2020 Category: Allergy & Immunology Authors: Innamarato P, Asby S, Morse J, Mackay A, Hall M, Kidd S, Nagle L, Sarnaik AA, Pilon-Thomas S Tags: J Immunol Source Type: research

Siglec-15 on Osteoclasts Is Crucial for Bone Erosion in Serum-Transfer Arthritis.
Nitschke L Abstract Siglec-15 is a conserved sialic acid-binding Ig-like lectin, which is expressed on osteoclasts. Deficiency of Siglec-15 leads to an impaired osteoclast development, resulting in a mild osteopetrotic phenotype. The role of Siglec-15 in arthritis is still largely unclear. To address this, we generated Siglec-15 knockout mice and analyzed them in a mouse arthritis model. We could show that Siglec-15 is directly involved in pathologic bone erosion in the K/BxN serum-transfer arthritis model. Histological analyses of joint destruction provided evidence for a significant reduction in bone erosion ar...
Source: Journal of Immunology - October 4, 2020 Category: Allergy & Immunology Authors: Korn MA, Schmitt H, Angermüller S, Chambers D, Seeling M, Lux UT, Brey S, Royzman D, Brückner C, Popp V, Percivalle E, Bäuerle T, Zinser E, Winkler TH, Steinkasserer A, Nimmerjahn F, Nitschke L Tags: J Immunol Source Type: research

Notch Regulates Innate Lymphoid Cell Plasticity during Human NK Cell Development.
Abstract Human NK cells develop in tonsils through discrete NK cell developmental intermediates (NKDIs), yet the mechanistic regulation of this process is unclear. We demonstrate that Notch activation in human tonsil-derived stage 3 (CD34-CD117+CD94-NKp80-) and 4A (CD34-CD117+/-CD94+NKp80-) NKDIs promoted non-NK innate lymphoid cell differentiation at the expense of NK cell differentiation. In contrast, stage 4B (CD34-CD117+/-CD94+NKp80+) NKDIs were NK cell lineage committed despite Notch activation. Interestingly, whereas NK cell functional maturation from stage 3 and 4A NKDIs was independent of Notch activation,...
Source: Journal of Immunology - October 4, 2020 Category: Allergy & Immunology Authors: Nalin AP, Kowalski JJ, Sprague AC, Schumacher BK, Gerhardt AG, Youssef Y, Vedantam KV, Zhang X, Siebel CW, Mace EM, Caligiuri MA, Mundy-Bosse BL, Freud AG Tags: J Immunol Source Type: research

Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid.
In this study, we characterized the inflammatory response in murine peritonitis and unexpectedly found the accumulation of adrenic acid (AdA), a poorly studied n-6 PUFA. Functional studies revealed that AdA potently inhibited the formation of the chemoattractant leukotriene B4 (LTB4), specifically in human neutrophils, and this correlated with a reduction of its precursor arachidonic acid (AA) in free form. AdA exposure in human monocyte-derived macrophages enhanced efferocytosis of apoptotic human neutrophils. In vivo, AdA treatment significantly alleviated arthritis in an LTB4-dependent murine arthritis model. Our findin...
Source: Journal of Immunology - October 1, 2020 Category: Allergy & Immunology Authors: Brouwers H, Jónasdóttir HS, Kuipers ME, Kwekkeboom JC, Auger JL, Gonzalez-Torres M, López-Vicario C, Clària J, Freysdottir J, Hardardottir I, Garrido-Mesa J, Norling LV, Perretti M, Huizinga TWJ, Kloppenburg M, Toes REM, Binstadt B, Giera M, Ioan-Facs Tags: J Immunol Source Type: research

IgA Triggers Cell Death of Neutrophils When Primed by Inflammatory Mediators.
We report that plasma-derived IgA efficiently triggers death of neutrophils primed by cytokines or TLR agonists. IgA-mediated programmed neutrophil death was PI3K-, p38 MAPK-, and JNK-dependent and evoked anti-inflammatory cytokines in macrophage cocultures. Neutrophils from patients with acute Crohn's disease, rheumatoid arthritis, or sepsis were susceptible to both IgA- and IVIG-mediated death. In contrast to IVIG, IgA did not promote cell death of quiescent neutrophils. Our findings suggest that plasma-derived IgA might provide a therapeutic option for the treatment of neutrophil-associated inflammatory disorders. ...
Source: Journal of Immunology - October 1, 2020 Category: Allergy & Immunology Authors: Wehrli M, Schneider C, Cortinas-Elizondo F, Verschoor D, Frias Boligan K, Adams OJ, Hlushchuk R, Engelmann C, Daudel F, Villiger PM, Seibold F, Yawalkar N, Vonarburg C, Miescher S, Lötscher M, Kaufmann T, Münz C, Mueller C, Djonov V, Simon HU, von Gunte Tags: J Immunol Source Type: research

The GM-CSF Released by Airway Epithelial Cells Orchestrates the Mucosal Adjuvant Activity of Flagellin.
In this study, we looked at how the airway epithelial cells (AECs) regulate the flagellin-dependent stimulation of Ag-specific CD4+ T cells and the Ab response in mice. Our results demonstrate that after sensing flagellin, AECs trigger the release of GM-CSF in a TLR5-dependent fashion and the doubling of the number of activated type 2 conventional dendritic cells (cDC2s) in draining lymph nodes. Furthermore, the neutralization of GM-CSF reduced cDC2s activation. This resulted in lower of Ag-specific CD4+ T cell count and Ab titers in mice. Our data indicate that during pulmonary immunization, the GM-CSF released by AECs or...
Source: Journal of Immunology - October 1, 2020 Category: Allergy & Immunology Authors: Vijayan A, Van Maele L, Fougeron D, Cayet D, Sirard JC Tags: J Immunol Source Type: research

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Authors: PMID: 32958705 [PubMed - in process] (Source: Journal of Immunology)
Source: Journal of Immunology - September 23, 2020 Category: Allergy & Immunology Tags: J Immunol Source Type: research

Dynamic Roles for IL-2-STAT5 Signaling in Effector and Regulatory CD4+ T Cell Populations.
Abstract CD4+ Th cells are responsible for orchestrating diverse, pathogen-specific immune responses through their differentiation into a number of subsets, including TH1, TH2, TH9, T follicular helper, T follicular regulatory, and regulatory T cells. The differentiation of each subset is guided by distinct regulatory requirements, including those derived from extracellular cytokine signals. IL-2 has emerged as a critical immunomodulatory cytokine that both positively and negatively affects the differentiation of individual Th cell subsets. IL-2 signals are propagated, in part, via activation of STAT5, which funct...
Source: Journal of Immunology - September 23, 2020 Category: Allergy & Immunology Authors: Jones DM, Read KA, Oestreich KJ Tags: J Immunol Source Type: research

Immune Response Resetting as a Novel Strategy to Overcome SARS-CoV-2-Induced Cytokine Storm.
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which rapidly became a pandemic of global proportions. Sepsis is commonly present with high lethality in the severe forms of the disease. The virus-induced cytokine storm puts the immune system in overdrive at the expense of the pathogen-specific immune response and is likely to underlie the most advanced COVID-19 clinical features, including sepsis-related multiple organ dysfunction as well as the pathophysiological changes found in the lungs. We review the major therapeutic strategies that have been ...
Source: Journal of Immunology - September 20, 2020 Category: Allergy & Immunology Authors: Nowill AE, de Campos-Lima PO Tags: J Immunol Source Type: research

Engineered Pigs Carrying a Gain-of-Function NLRP3 Homozygous Mutation Can Survive to Adulthood and Accurately Recapitulate Human Systemic Spontaneous Inflammatory Responses.
In this study, an NLRP3 gain-of-function pig model carrying a homozygous R259W mutation was generated by combining CRISPR/Cpf1-mediated somatic cell genome editing with nuclear transfer. The newborn NLRP3 R259W homozygous piglets showed early mortality, poor growth, and spontaneous systemic inflammation symptoms, including skin lesion, joint inflammation, severe contracture, and inflammation-mediated multiorgan failure. Severe myocardial fibrosis was also observed. The tissues of inflamed skins and several organs showed significantly increased expressions of NLRP3, Caspase-1, and inflammation-associated cytokines and facto...
Source: Journal of Immunology - September 20, 2020 Category: Allergy & Immunology Authors: Li W, Shi L, Zhuang Z, Wu H, Lian M, Chen Y, Li L, Ge W, Jin Q, Zhang Q, Zhao Y, Liu Z, Ouyang Z, Ye Y, Li Y, Wang H, Liao Y, Quan L, Xiao L, Lai L, Meng G, Wang K Tags: J Immunol Source Type: research

TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling.
Abstract Lung fibrosis and tissue remodeling are features of chronic diseases such as severe asthma, idiopathic pulmonary fibrosis, and systemic sclerosis. However, fibrosis-targeted therapies are currently limited. We demonstrate in mouse models of allergen- and bleomycin-driven airway inflammation that neutralization of the TNF family cytokine TL1A through Ab blocking or genetic deletion of its receptor DR3 restricted increases in peribronchial smooth muscle mass and accumulation of lung collagen, primary features of remodeling. TL1A was found as a soluble molecule in the airways and expressed on the surface of ...
Source: Journal of Immunology - September 20, 2020 Category: Allergy & Immunology Authors: Herro R, Miki H, Sethi GS, Mills D, Mehta AK, Nguyen XX, Feghali-Bostwick C, Miller M, Broide DH, Soloff R, Croft M Tags: J Immunol Source Type: research

Hepcidin Is Essential for Alveolar Macrophage Function and Is Disrupted by Smoke in a Murine Chronic Obstructive Pulmonary Disease Model.
In this study, using a murine model of smoke-induced COPD, we demonstrate that lung and circulating hepcidin levels are inhibited by cigarette smoke. We show that cigarette smoke exposure increases erythropoietin and bone marrow-derived erythroferrone and leads to expanded but inefficient erythropoiesis in murine bone marrow and an increase in ferroportin on alveolar macrophages (AMs). AMs from smokers and subjects with COPD display increased expression of ferroportin as well as hepcidin. Notably, murine AMs exposed to smoke fail to increase hepcidin in response to Gram-negative or Gram-positive infection. Loss of hepcidin...
Source: Journal of Immunology - September 20, 2020 Category: Allergy & Immunology Authors: Perez E, Baker JR, Di Giandomenico S, Kermani P, Parker J, Kim K, Yang J, Barnes PJ, Vaulont S, Scandura JM, Donnelly LE, Stout-Delgado H, Cloonan SM Tags: J Immunol Source Type: research

Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection.
In this study, we employed a comprehensive transcriptional/translational profiling strategy to delineate the identities, expression patterns, and dynamic regulation of chemokines produced by murine pathogen-specific TM CD8+TM, and to a lesser extent CD4+TM, are a prodigious source for six select chemokines (CCL1/3/4/5, CCL9/10, and XCL1) that collectively constitute a prominent and largely invariant signature across acute and chronic infections. Notably, constitutive CCL5 expression by CD8+TM serves as a unique functional imprint of prior antigenic experience; induced CCL1 production identifies highly polyfunctional CD8+ a...
Source: Journal of Immunology - September 17, 2020 Category: Allergy & Immunology Authors: Davenport B, Eberlein J, Nguyen TT, Victorino F, van der Heide V, Kuleshov M, Ma'ayan A, Kedl R, Homann D Tags: J Immunol Source Type: research

Foxp3+ Regulatory T Cell Depletion after Nonablative Oligofractionated Irradiation Boosts the Abscopal Effects in Murine Malignant Mesothelioma.
In this study, we found that the upregulation of Foxp3+ regulatory T cells (Tregs) in the mesothelioma tumor microenvironment after nonablative oligofractionated irradiation significantly limited the success of irradiation. Using DEREG mice, which allow conditional and efficient depletion of Foxp3+ Tregs by diphtheria toxin injection, we observed that transient Foxp3+ Treg depletion immediately after nonablative oligofractionated irradiation provided synergistic local control and biased the T cell repertoire toward central and effector memory T cells, resulting in long-term cure. Furthermore, this combination therapy showe...
Source: Journal of Immunology - September 17, 2020 Category: Allergy & Immunology Authors: Kohno M, Murakami J, Wu L, Chan ML, Yun Z, Cho BCJ, de Perrot M Tags: J Immunol Source Type: research

TRIM21 Is Targeted for Chaperone-Mediated Autophagy during Salmonella Typhimurium Infection.
In this study, we investigated the role of TRIM21 upon S Typhimurium infection of murine bone marrow-derived macrophages. Although Trim21 expression was induced in an IFN-I-dependent manner, we found that TRIM21 levels were mainly regulated posttranscriptionally. Following TLR4 activation, TRIM21 was transiently degraded via the lysosomal pathway by chaperone-mediated autophagy (CMA). However, S Typhimurium-induced mTORC2 signaling led to phosphorylation of Akt at S473, which subsequently impaired TRIM21 degradation by attenuating CMA. Elevated TRIM21 levels promoted macrophage death associated with reduced transcription o...
Source: Journal of Immunology - September 17, 2020 Category: Allergy & Immunology Authors: Hos NJ, Fischer J, Hos D, Hejazi Z, Calabrese C, Ganesan R, Murthy AMV, Rybniker J, Kumar S, Krönke M, Robinson N Tags: J Immunol Source Type: research

A Critical Role for the CXCL3/CXCL5/CXCR2 Neutrophilic Chemotactic Axis in the Regulation of Type 2 Responses in a Model of Rhinoviral-Induced Asthma Exacerbation.
Abstract Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and their expression in the asthmatic lung is associated with steroid-insensitive type 2 inflammatory signatures. Currently, the role of CXCL3 and CXCL5 in regulating neutrophilic and type 2 responses in viral-induced asthma exacerbation is unknown. Inhibition of CXCL3 or CXCL5 with silencing RNAs in a mouse model o...
Source: Journal of Immunology - September 17, 2020 Category: Allergy & Immunology Authors: Sokulsky LA, Garcia-Netto K, Nguyen TH, Girkin JLN, Collison A, Mattes J, Kaiko G, Liu C, Bartlett NW, Yang M, Foster PS Tags: J Immunol Source Type: research

Efficient Expansion of Human Granzyme B-Expressing B Cells with Potent Regulatory Properties.
Abstract Granzyme B-expressing B cells have been shown to be an important regulatory B cell subset in humans. However, it is unclear which subpopulations of B cells express GZMB under normal conditions and which protocols effectively induce ex vivo expansion of GZMB+ B cells. We found that in the peripheral blood of normal individuals, plasmablasts were the major B cell subpopulation that expressed GZMB. However, when using an in vitro plasmablast differentiation protocol, we obtained only 2% GZMB+ B cells. Nevertheless, using an expansion mixture containing IL-21, anti-BCR, CpG oligodeoxynucleotide, CD40L, and IL...
Source: Journal of Immunology - September 17, 2020 Category: Allergy & Immunology Authors: Chesneau M, Mai HL, Danger R, Le Bot S, Nguyen TV, Bernard J, Poullaouec C, Guerrif P, Conchon S, Giral M, Charreau B, Degauque N, Brouard S Tags: J Immunol Source Type: research

Chemokine Signatures of Pathogen-Specific T Cells I: Effector T Cells.
In this study, using different in vivo mouse models of viral and bacterial infection as well as protective vaccination, we have defined the entire spectrum of chemokines produced by pathogen-specific CD8+ and CD4+T effector cells and delineated several unique properties pertaining to the temporospatial organization of chemokine expression patterns, synthesis and secretion kinetics, and cooperative regulation. Collectively, our results position the "T cell chemokine response" as a notably prominent, largely invariant, yet distinctive force at the forefront of pathogen-specific effector T cell activities and establ...
Source: Journal of Immunology - September 17, 2020 Category: Allergy & Immunology Authors: Eberlein J, Davenport B, Nguyen TT, Victorino F, Jhun K, van der Heide V, Kuleshov M, Ma'ayan A, Kedl R, Homann D Tags: J Immunol Source Type: research

Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer.
Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer. J Immunol. 2020 Sep 16;: Authors: Steinberger KJ, Forget MA, Bobko AA, Mihalik NE, Gencheva M, Roda JM, Cole SL, Mo X, Hoblitzell EH, Evans R, Gross AC, Moldovan L, Marsh CB, Khramstov VV, Eubank TD Abstract Tie2-expressing monocytes/macrophages (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer. Because of the hypoxic nature of solid tumors, we investigated if oxygen, via hypoxia-inducible transcription ...
Source: Journal of Immunology - September 15, 2020 Category: Allergy & Immunology Authors: Steinberger KJ, Forget MA, Bobko AA, Mihalik NE, Gencheva M, Roda JM, Cole SL, Mo X, Hoblitzell EH, Evans R, Gross AC, Moldovan L, Marsh CB, Khramstov VV, Eubank TD Tags: J Immunol Source Type: research

A Genetic Model of Constitutively Active Integrin CD11b/CD18.
Abstract Pharmacological activation of integrin CD11b/CD18 (αMβ2, Mac-1, and CR3) shows anti-inflammatory benefits in a variety of animal models of human disease, and it is a novel therapeutic strategy. Reasoning that genetic models can provide an orthogonal and direct system for the mechanistic study of CD11b agonism, we present in this study, to our knowledge, a novel knock-in model of constitutive active CD11b in mice. We genetically targeted the Itgam gene (which codes for CD11b) to introduce a point mutation that results in the I332G substitution in the protein. The I332G mutation in CD11b promotes...
Source: Journal of Immunology - September 15, 2020 Category: Allergy & Immunology Authors: Martinez L, Li X, Ramos-Echazabal G, Faridi H, Zigmond ZM, Santos Falcon N, Hernandez DR, Shehadeh SA, Velazquez OC, Gupta V, Vazquez-Padron RI Tags: J Immunol Source Type: research

Reactive Oxidative Species-Modulated Ca2+ Release Regulates β2 Integrin Activation on CD4+ CD28null T Cells of Acute Coronary Syndrome Patients.
In this study, we show that in human T cells, SDF-1α-mediated β2 integrin activation is driven by a, so far, not-described reactive oxidative species (ROS)-regulated calcium influx. Furthermore, we show that CD4+CD28null T cells represent a highly reactive subset showing 25-fold stronger β2 integrin activation upon SDF-1α stimulation compared with CD28+ T cells. Interestingly, ROS-dependent Ca release was much more prevalent in the pathogenetically pivotal CD28null subset compared with the CD28+ T cells, whereas the established mediators of the classical pathways for β2 integrin activation (PKC, ...
Source: Journal of Immunology - September 15, 2020 Category: Allergy & Immunology Authors: Samstag Y, Bogert NV, Wabnitz GH, Din S, Therre M, Leuschner F, Katus HA, Konstandin MH Tags: J Immunol Source Type: research

A Complement C3-Specific Nanobody for Modulation of the Alternative Cascade Identifies the C-Terminal Domain of C3b as Functional in C5 Convertase Activity.
In this study, we describe the nanobody hC3Nb3, which is specific for the C-terminal C345c domain of human and mouse complement component C3/C3b/C3c and potently inhibits C3 cleavage by the alternative pathway. A high-resolution structure of the hC3Nb3-C345c complex explains how the nanobody blocks proconvertase assembly. Surprisingly, although the nanobody does not affect classical pathway-mediated C3 cleavage, hC3Nb3 inhibits classical pathway-driven hemolysis, suggesting that the C-terminal domain of C3b has an important function in classical pathway C5 convertase activity. The hC3Nb3 nanobody binds C3 with low nanomola...
Source: Journal of Immunology - September 15, 2020 Category: Allergy & Immunology Authors: Pedersen H, Jensen RK, Jensen JMB, Fox R, Pedersen DV, Olesen HG, Hansen AG, Christiansen D, Mazarakis SMM, Lojek N, Hansen P, Gadeberg TAF, Zarantonello A, Laursen NS, Mollnes TE, Johnson MB, Stevens B, Thiel S, Andersen GR Tags: J Immunol Source Type: research

Correction: A Critical Role of Costimulation during Intrathymic Development of Invariant NK T Cells.
PMID: 32938728 [PubMed - as supplied by publisher] (Source: Journal of Immunology)
Source: Journal of Immunology - September 15, 2020 Category: Allergy & Immunology Authors: Chung Y, Nurieva R, Esashi E, Wang YH, Zhou D, Gapin L, Dong C Tags: J Immunol Source Type: research

T Cells from NOD-PerIg Mice Target Both Pancreatic and Neuronal Tissue.
Abstract It has become increasingly appreciated that autoimmune responses against neuronal components play an important role in type 1 diabetes (T1D) pathogenesis. In fact, a large proportion of islet-infiltrating B lymphocytes in the NOD mouse model of T1D produce Abs directed against the neuronal type III intermediate filament protein peripherin. NOD-PerIg mice are a previously developed BCR-transgenic model in which virtually all B lymphocytes express the H and L chain Ig molecules from the intra-islet-derived anti-peripherin-reactive hybridoma H280. NOD-PerIg mice have accelerated T1D development, and PerIg B ...
Source: Journal of Immunology - September 15, 2020 Category: Allergy & Immunology Authors: Racine JJ, Chapman HD, Doty R, Cairns BM, Hines TJ, Tadenev ALD, Anderson LC, Green T, Dyer ME, Wotton JM, Bichler Z, White JK, Ettinger R, Burgess RW, Serreze DV Tags: J Immunol Source Type: research

Staphylococcal Enterotoxin C2 Mutant-Directed Fatty Acid and Mitochondrial Energy Metabolic Programs Regulate CD8+ T Cell Activation.
In this study, we found that ST-4, but not SEC2, could induce proliferation of purified CD8+ T cell from BALB/c mice in Vβ8.2- and -8.3-specific manners. Results of gas chromatography-mass spectroscopy analysis showed that fatty acid contents in CD8+ T cells were increased after ST-4 stimulation. Flow cytometry and Seahorse analyses showed that ST-4 significantly promoted mitochondrial energy metabolism in CD8+ T cells. We also observed significantly upregulated levels of gene transcripts for fatty acid uptake and synthesis, and significantly increased protein expression levels of fatty acid and mitochondrial metaboli...
Source: Journal of Immunology - September 15, 2020 Category: Allergy & Immunology Authors: Fu X, Xu M, Zhang H, Li Y, Li Y, Zhang C Tags: J Immunol Source Type: research

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Authors: PMID: 32900884 [PubMed - in process] (Source: Journal of Immunology)
Source: Journal of Immunology - September 11, 2020 Category: Allergy & Immunology Tags: J Immunol Source Type: research

Nutritional Modulation of the Microbiome and Immune Response.
Abstract The evolution of the immune system, diet, and the microbiome are interconnected. Dietary metabolites modulate the cells of the immune system both directly and indirectly via shifts in the composition of the intestinal microbiota and its products. As a result, overconsumption and malnutrition can have substantial effects on immune responses and inflammation. In resource-rich nations, diets high in processed foods, fat, and sugar can contribute to chronic inflammatory conditions, which are on the rise worldwide. Conversely, in resource-poor countries, malnutrition associated with food insecurity can lead to...
Source: Journal of Immunology - September 11, 2020 Category: Allergy & Immunology Authors: Burr AHP, Bhattacharjee A, Hand TW Tags: J Immunol Source Type: research

p53 Hinders CRISPR/Cas9-Mediated Targeted Gene Disruption in Memory CD8 T Cells In Vivo.
In this study, we show that CRISPR/Cas9-mediated gene editing in memory CD8 T cells precludes their proliferation after Ag re-encounter in vivo. This defect is mediated by the proapoptotic transcription factor p53, a sensor of DNA damage. Temporarily inhibiting p53 function offers a window of opportunity for the memory CD8 T cells to repair the DNA damage, facilitating robust recall responses on Ag re-encounter. We demonstrate this by functionally altering memory CD8 T cells using CRISPR/Cas9-mediated targeted gene disruption under the aegis of p53siRNA in the mouse model. Our approach thus adapts the CRISPR/Cas9 technolog...
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Kurup SP, Moioffer SJ, Pewe LL, Harty JT Tags: J Immunol Source Type: research

Immunization with Mycobacterium tuberculosis-Specific Antigens Bypasses T Cell Differentiation from Prior Bacillus Calmette-Gu érin Vaccination and Improves Protection in Mice.
Immunization with Mycobacterium tuberculosis-Specific Antigens Bypasses T Cell Differentiation from Prior Bacillus Calmette-Guérin Vaccination and Improves Protection in Mice. J Immunol. 2020 Sep 04;: Authors: Aagaard C, Knudsen NPH, Sohn I, Izzo AA, Kim H, Kristiansen EH, Lindenstrøm T, Agger EM, Rasmussen M, Shin SJ, Rosenkrands I, Andersen P, Mortensen R Abstract Despite the fact that the majority of people in tuberculosis (TB)-endemic areas are vaccinated with the Bacillus Calmette-Guérin (BCG) vaccine, TB remains the leading infectious cause of death. Data from both animal mo...
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Aagaard C, Knudsen NPH, Sohn I, Izzo AA, Kim H, Kristiansen EH, Lindenstrøm T, Agger EM, Rasmussen M, Shin SJ, Rosenkrands I, Andersen P, Mortensen R Tags: J Immunol Source Type: research

A Cross-Species Reactive TIGIT-Blocking Antibody Fc Dependently Confers Potent Antitumor Effects.
In this study, we report the development of a human mAb, T4, which recognizes both human and mouse TIGIT and blocks the interaction of TIGIT with its ligand CD155 in both species. The T4 Ab targets the segment connecting F and G strands of TIGIT's extracellular IgV domain, and we show in studies with mouse tumor models that the T4 Ab exerts strong antitumor activity and induces durable immune memory against various tumor types. Mechanistically, we demonstrate that the T4 Ab's antitumor effects are mediated via multiple immunological impacts, including a CD8+ T immune response and Fc-mediated effector functions, through NK ...
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Yang F, Zhao L, Wei Z, Yang Y, Liu J, Li Y, Tian X, Liu X, Lü X, Sui J Tags: J Immunol Source Type: research

FLT3 Ligand Is Dispensable for the Final Stage of Type 1 Conventional Dendritic Cell Differentiation.
Abstract Conventional dendritic cells (cDCs) are comprised of two major subsets, type 1 cDC (cDC1) and type 2 cDC (cDC2). As each cDC subset differentially influences the nature of immune responses, we sought factors that would allow the manipulation of their relative abundance. Notably, cDC1 are less abundant than cDC2 in both lymphoid and nonlymphoid organs. We demonstrate that this bias is already apparent in bone marrow precommitted precursors. However, comparison of five common inbred strains revealed a disparity in precursor-product relationship, in which mice with fewer precursors to cDC1 had more cDC1. Thi...
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Audiger C, Lesage S Tags: J Immunol Source Type: research

PIK3IP1 Promotes Extrafollicular Class Switching in T-Dependent Immune Responses.
In this study, we define the consequences of B cell-specific deletion of PIK3IP1. B cell development, basal Ig levels, and T-independent responses were unaffected by loss of PIK3IP1. However, there was a significant delay in the production of IgG during T-dependent responses, and secondary responses were impaired. This is likely due to a role for PIK3IP1 in the extrafollicular response because germinal center formation and affinity maturation were normal, and PIK3IP1 is not appreciably expressed in germinal center B cells. Consistent with a role early in the response, PIK3IP1 was downregulated at late time points after B c...
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Ottens K, Schneider J, Kane LP, Satterthwaite AB Tags: J Immunol Source Type: research

Canonical Wnts Mediate CD8+ T Cell Noncytolytic Anti-HIV-1 Activity and Correlate with HIV-1 Clinical Status.
This study demonstrates that canonical Wnt signaling inhibits HIV and significantly correlates with HIV controller status. PMID: 32887752 [PubMed - as supplied by publisher] (Source: Journal of Immunology)
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Wallace J, Narasipura SD, Sha BE, French AL, Al-Harthi L Tags: J Immunol Source Type: research

Antibodies against Phosphorylcholine and Malondialdehyde during the First Two Years of Life.
ing;rd J Abstract Abs against phosphorylcholine (anti-PC) and Abs against malondialdehyde (anti-MDA) may be protective in chronic inflammation, like atherosclerosis and cardiovascular disease. It is not known how they develop early in life. Ab titers were measured using ELISA in healthy women (n = 105; born into life study) and their children. Plasma samples were collected from the mothers before conception and from the children at birth as well as at 1 and 2 y after birth. Extracted Abs were compared using a proteomics de novo sequencing approach. It was observed that children were born with very low levels of Ig...
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Thiagarajan D, Lundström SL, Pershagen G, Almqvist Malmros C, Andolf E, Hedman A, Berg O, Oparina N, Frostegård J Tags: J Immunol Source Type: research

Antibody Responses to SARS-CoV-2: Let's Stick to Known Knowns.
Abstract The scale of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has thrust immunology into the public spotlight in unprecedented ways. In this article, which is part opinion piece and part review, we argue that the normal cadence by which we discuss science with our colleagues failed to properly convey likelihoods of the immune response to SARS-CoV-2 to the public and the media. As a result, biologically implausible outcomes were given equal weight as the principles set by decades of viral immunology. Unsurprisingly, questionable results and alarmist news media articles have filled ...
Source: Journal of Immunology - September 3, 2020 Category: Allergy & Immunology Authors: Baumgarth N, Nikolich-Žugich J, Lee FE, Bhattacharya D Tags: J Immunol Source Type: research

Combining Three-Dimensional Modeling with Artificial Intelligence to Increase Specificity and Precision in Peptide-MHC Binding Predictions.
In this study, we present a rapid, predictive computational approach that combines a popular, sequence-based artificial neural network method, NetMHCpan 4.0, with three-dimensional structural modeling. We find that the ensembles of bound peptide conformations generated by the programs MODELLER and Rosetta FlexPepDock are less variable in geometry for strong binders than for low-affinity peptides. In tests on 1271 peptide sequences for which the experimental dissociation constants of binding to the well-characterized murine MHC allele H-2Db are known, by applying thresholds for geometric fluctuations the structure-based app...
Source: Journal of Immunology - September 1, 2020 Category: Allergy & Immunology Authors: Aranha MP, Jewel YSM, Beckman RA, Weiner LM, Mitchell JC, Parks JM, Smith JC Tags: J Immunol Source Type: research

Higher Frequency and Increased Expression of Molecules Associated with Suppression on T Regulatory Cells from Newborn Compared with Adult Nonhuman Primates.
In this study, we used a newborn nonhuman primate model to assess Treg populations present at multiple sites with regard to frequency and phenotype in comparison with those present in adult animals. We found that Foxp3+ cells were more highly represented in the T cell compartment of newborn nonhuman primates for all sites examined (i.e., the spleen, lung, and circulation). In the spleen and circulation, newborn-derived Tregs expressed significantly higher levels of Foxp3 and CD25 compared with adults, consistent with an effector phenotype. Strikingly, the phenotype of Tregs in the lungs of adult and infant animals was rela...
Source: Journal of Immunology - September 1, 2020 Category: Allergy & Immunology Authors: Holbrook BC, Alexander-Miller MA Tags: J Immunol Source Type: research

Expansion of SARS-CoV-2-Specific Antibody-Secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients.
In this study, we analyzed Ab-secreting cell and Ab responses in 20 hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19 and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific Ab-secreting cells in all 20 COVID-19 patients using a multicolor FluoroSpot Assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing Abs by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG, and IgM Ab levels positively correlated with SARS-CoV-2-neutralizing Ab titers, sugg...
Source: Journal of Immunology - September 1, 2020 Category: Allergy & Immunology Authors: Varnaitė R, García M, Glans H, Maleki KT, Sandberg JT, Tynell J, Christ W, Lagerqvist N, Asgeirsson H, Ljunggren HG, Ahlén G, Frelin L, Sällberg M, Blom K, Klingström J, Gredmark-Russ S Tags: J Immunol Source Type: research

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Authors: PMID: 32839210 [PubMed - in process] (Source: Journal of Immunology)
Source: Journal of Immunology - August 27, 2020 Category: Allergy & Immunology Tags: J Immunol Source Type: research

Damage-Associated Molecular Patterns and the Systemic Immune Consequences of Severe Thermal Injury.
Abstract Thermal injury is often associated with a proinflammatory state resulting in serious complications. After a burn, the innate immune system is activated with subsequent immune cell infiltration and cytokine production. Although the innate immune response is typically beneficial, an excessive activation leads to cytokine storms, multiple organ failure, and even death. This overwhelming immune response is regulated by damage-associated molecular patterns (DAMPs). DAMPs are endogenous molecules that are actively secreted by immune cells or passively released by dead or dying cells that can bind to pathogen re...
Source: Journal of Immunology - August 27, 2020 Category: Allergy & Immunology Authors: Comish PB, Carlson D, Kang R, Tang D Tags: J Immunol Source Type: research

ArhGAP15, a RacGAP, Acts as a Temporal Signaling Regulator of Mac-1 Affinity in Sterile Inflammation.
In conclusion, ArhGAP15 is involved in the time-dependent regulation of leukocyte postadhesion in sterile inflammation. PMID: 32839212 [PubMed - in process] (Source: Journal of Immunology)
Source: Journal of Immunology - August 27, 2020 Category: Allergy & Immunology Authors: Margraf A, Cappenberg A, Vadillo E, Ludwig N, Thomas K, Körner K, Zondler L, Rossaint J, Germena G, Hirsch E, Zarbock A Tags: J Immunol Source Type: research

Blockade of the G-CSF Receptor Is Protective in a Mouse Model of Renal Ischemia-Reperfusion Injury.
In this study, we investigated whether targeting neutrophils with a neutralizing mAb to G-CSFR would reduce inflammation and protect against injury in a mouse model of warm renal IRI. Mice were treated with anti-G-CSFR 24 h prior to 22-min unilateral renal ischemia. Renal function and histology, complement activation, and expression of kidney injury markers, and inflammatory mediators were assessed 24 h after reperfusion. Treatment with anti-G-CSFR protected against renal IRI in a dose-dependent manner, significantly reducing serum creatinine and urea, tubular injury, neutrophil and macrophage infiltration, and complement ...
Source: Journal of Immunology - August 27, 2020 Category: Allergy & Immunology Authors: McRae JL, Vikstrom IB, Bongoni AK, Salvaris EJ, Fisicaro N, Ng M, Alhamdoosh M, Baz Morelli A, Cowan PJ, Pearse MJ Tags: J Immunol Source Type: research

Collagen Density Modulates the Immunosuppressive Functions of Macrophages.
In this study, we investigated whether the collagen density could modulate the immunosuppressive activity of TAMs. The murine macrophage cell line RAW 264.7 was three-dimensionally cultured in collagen matrices of low and high collagen densities mimicking healthy and tumor tissue, respectively. Collagen density did not affect proliferation or viability of the macrophages. However, whole-transcriptome analysis revealed a striking response to the surrounding collagen density, including the regulation of immune regulatory genes and genes encoding chemokines. These transcriptional changes were shown to be similar in murine bon...
Source: Journal of Immunology - August 27, 2020 Category: Allergy & Immunology Authors: Larsen AMH, Kuczek DE, Kalvisa A, Siersbæk MS, Thorseth ML, Johansen AZ, Carretta M, Grøntved L, Vang O, Madsen DH Tags: J Immunol Source Type: research

Regulatory T Cell Stability and Migration Are Dependent on mTOR.
In this study, we revisited this question by using mice that have a specific deletion of mTOR in Treg. These mice spontaneously develop a severe and systemic inflammation. We show that mTOR expression by Treg is critical for their differentiation into effector Treg and their migration into nonlymphoid tissues. We also reveal that mTOR-deficient Treg have reduced stability. This loss of Foxp3 expression is associated with partial Foxp3 DNA remethylation, which may be due to an increased activity of the glutaminolysis pathway. Thus, our work shows that mTOR is crucial for Treg differentiation, migration, and identity and tha...
Source: Journal of Immunology - August 23, 2020 Category: Allergy & Immunology Authors: Vallion R, Divoux J, Glauzy S, Ronin E, Lombardi Y, Lubrano di Ricco M, Grégoire S, Nemazanyy I, Durand A, Fradin D, Lucas B, Salomon BL Tags: J Immunol Source Type: research