Comment on "Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1".
Comment on "Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1". J Immunol. 2019 Oct 15;203(8):2029 Authors: Kang J, Warren AN PMID: 31591257 [PubMed - in process] (Source: Journal of Immunology)
Source: Journal of Immunology - October 10, 2019 Category: Allergy & Immunology Authors: Kang J, Warren AN Tags: J Immunol Source Type: research

Response to Comment on "Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1".
Response to Comment on "Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1". J Immunol. 2019 Oct 15;203(8):2029-2030 Authors: Dopler A, Guntau L, Harder MJ, Palmer A, Höchsmann B, Schrezenmeier H, Simmet T, Huber-Lang M, Schmidt CQ PMID: 31591258 [PubMed - in process] (Source: Journal of Immunology)
Source: Journal of Immunology - October 10, 2019 Category: Allergy & Immunology Authors: Dopler A, Guntau L, Harder MJ, Palmer A, Höchsmann B, Schrezenmeier H, Simmet T, Huber-Lang M, Schmidt CQ Tags: J Immunol Source Type: research

Regulatory T Cell Development in the Thymus.
In this study, we review cellular and molecular determinants of Treg cell development in the thymus. We focus on the evidence for a self-antigen-focused Treg cell repertoire as well as the APCs responsible for presenting self-antigens to developing thymocytes. We also cover the contribution of different cytokines to thymic Treg development and the cellular populations that produce these cytokines. Finally, we update the originally proposed "two-step" model of thymic Treg differentiation by incorporating new evidence demonstrating that Treg cells develop from two Treg progenitor populations and discuss the functio...
Source: Journal of Immunology - October 10, 2019 Category: Allergy & Immunology Authors: Owen DL, Sjaastad LE, Farrar MA Tags: J Immunol Source Type: research

STAT3 Inhibition Partly Abolishes IL-33-Induced Bone Marrow-Derived Monocyte Phenotypic Transition into Fibroblast Precursor and Alleviates Experimental Renal Interstitial Fibrosis.
In this study, we tested the effect of a new STAT3 inhibitor, BP-1-102, on monocyte-to-fibrocyte transition and the progression of renal interstitial fibrosis. We tested the effect of BP-1-102 in a mouse model of unilateral ureteral obstruction in vivo and IL-33-treated bone marrow-derived monocytes in vitro. BP-1-102 treatment alleviated renal interstitial fibrosis, reduced collagen deposition and extracellular matrix protein production, inhibited inflammatory cell infiltration, suppressed the percentage of CD45+ PDGFRβ+, CD45+ CD34- Col I+ and CD45+ CD11b+ Col I+ cells within the obstructed kidney and reduced the mR...
Source: Journal of Immunology - October 7, 2019 Category: Allergy & Immunology Authors: Zhu F, Bai X, Hong Q, Cui S, Wang X, Xiao F, Li J, Zhang L, Dong Z, Wang Y, Cai G, Chen X Tags: J Immunol Source Type: research

Distinct Host-Mycobacterial Pathogen Interactions between Resistant Adult and Tolerant Tadpole Life Stages of Xenopus laevis.
In this study, we developed an infection model system in the amphibian Xenopus laevis to study host responses to M. marinum at two distinct life stages, tadpole and adult. Adult frogs possess efficient conventional T cell-mediated immunity, whereas tadpoles predominantly rely on iT cells. We hypothesized that tadpoles are more susceptible and elicit weaker immune responses to M. marinum than adults. However, our results show that, although anti-M. marinum immune responses between tadpoles and adults are different, tadpoles are as resistant to M. marinum inoculation as adult frogs. M. marinum inoculation triggered a robust ...
Source: Journal of Immunology - October 7, 2019 Category: Allergy & Immunology Authors: Rhoo KH, Edholm ES, Forzán MJ, Khan A, Waddle AW, Pavelka MS, Robert J Tags: J Immunol Source Type: research

High GILT Expression and an Active and Intact MHC Class II Antigen Presentation Pathway Are Associated with Improved Survival in Melanoma.
Abstract The MHC class I Ag presentation pathway in melanoma cells has a well-established role in immune-mediated destruction of tumors. However, the clinical significance of the MHC class II Ag presentation pathway in melanoma cells is less clear. In Ag-presenting cells, IFN-γ-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of multiple melanoma Ags. Although not expressed in benign melanocytes of nevi, GILT and MHC class II expression is induced in malignant melanocytes in a portion of melanoma specimens. Analysis of The Cancer Genome Atlas cutaneous melanoma ...
Source: Journal of Immunology - October 7, 2019 Category: Allergy & Immunology Authors: Buetow KH, Meador LR, Menon H, Lu YK, Brill J, Cui H, Roe DJ, DiCaudo DJ, Hastings KT Tags: J Immunol Source Type: research

The Role of Kupffer Cells as Mediators of Adipose Tissue Lipolysis.
In this study, we found that depletion of KCs in vivo led to enhanced lipolysis in adipose tissue by increasing the expression of FGF21, a metabolic regulator, in hepatocytes. IL-1β secreted from KCs contributed to the suppression of FGF21 expression in hepatocytes. FGF21 overexpression led to a lean phenotype and enhanced lipolysis in mice. KC depletion resulted in a lack of IL-1β signaling in the liver, leading to elevated expression of FGF21 in hepatocytes. FGF21 promoted lipolysis in adipose tissue and led to hyperlipidemia and decreased body weight. The secretion of IL-1β in KCs was mediated by bacteria...
Source: Journal of Immunology - October 4, 2019 Category: Allergy & Immunology Authors: Ma W, Zhao D, He F, Tang L Tags: J Immunol Source Type: research

Crlz-1 Controls Germinal Center Reaction by Relaying a Wnt Signal to the Bcl-6 Expression in Centroblasts during Humoral Immune Responses.
Abstract Crlz-1 was expressed along with Wnt3a in the rapidly proliferating centroblasts within the dark zone of germinal center (GC) during humoral immune responses. Significantly, Crlz-1 relayed a Wnt/β-catenin signal to the expression of Bcl-6, the master regulator of centroblasts, by mobilizing the cytoplasmic CBFβ into the nucleus to allow Runx/CBFβ heterodimerization and its subsequent binding to the Bcl-6 promoter. The knockdown of Crlz-1 or β-catenin, as well as inhibition of Wnt signaling in the centroblasts, led to the decreased expression of Bcl-6 and, thereby, the altered expression...
Source: Journal of Immunology - October 4, 2019 Category: Allergy & Immunology Authors: Choi SY, Pi JH, Park SK, Kang CJ Tags: J Immunol Source Type: research

Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung.
Abstract Alternatively activated macrophages are essential effector cells during type 2 immunity and tissue repair following helminth infections. We previously showed that Ym1, an alternative activation marker, can drive innate IL-1R-dependent neutrophil recruitment during infection with the lung-migrating nematode, Nippostrongylus brasiliensis, suggesting a potential role for the inflammasome in the IL-1-mediated innate response to infection. Although inflammasome proteins such as NLRP3 have important proinflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We ther...
Source: Journal of Immunology - October 4, 2019 Category: Allergy & Immunology Authors: Chenery AL, Alhallaf R, Agha Z, Ajendra J, Parkinson JE, Cooper MM, Chan BHK, Eichenberger RM, Dent LA, Robertson AAB, Kupz A, Brough D, Loukas A, Sutherland TE, Allen JE, Giacomin PR Tags: J Immunol Source Type: research

IL-36 γ Is a Key Regulator of Neutrophil Infiltration in the Vaginal Microenvironment and Limits Neuroinvasion in Genital HSV-2 Infection.
In this report, we reveal that IL-36γ specifically induces transient neutrophil infiltration but does not impact monocyte and macrophage recruitment. Using IL-36γ-/- mice in a lethal HSV-2 challenge model, we show that neutrophil counts are significantly reduced at 1 and 2 d postinfection and that KC-mediated mature neutrophil recruitment is impaired in IL-36γ-/- mice. Additionally, IL-36γ-/- mice develop genital disease more rapidly, have significantly reduced survival time, and exhibit an increased incidence of hind limb paralysis that is linked to productive HSV-2 infection in the brain stem. IL-...
Source: Journal of Immunology - October 2, 2019 Category: Allergy & Immunology Authors: Gardner JK, Swaims-Kohlmeier A, Herbst-Kralovetz MM Tags: J Immunol Source Type: research

Peroxisome Proliferator-Activated Receptor- δ Acts within Peripheral Myeloid Cells to Limit Th Cell Priming during Experimental Autoimmune Encephalomyelitis.
In this study, we studied the specific involvement of PPAR-δ in myeloid cells during EAE using mice that had Cre-mediated excision of floxed Ppard driven by the lysozyme M (LysM) promoter (LysM Cre :Ppard fl/fl). We observed that LysM Cre :Ppard fl/fl mice were more susceptible to EAE and developed a more severe course of this disease compared with Ppard fl/fl controls. The more severe EAE in LysM Cre :Ppard fl/fl mice was associated with an increased accumulation of pathogenic CD4+ T cells in the CNS and enhanced myelin-specific Th1 and Th17 responses in the periphery. Adoptive transfer EAE studies linked this EAE p...
Source: Journal of Immunology - October 2, 2019 Category: Allergy & Immunology Authors: Drohomyrecky PC, Doroshenko ER, Akkermann R, Moshkova M, Yi TJ, Zhao FL, Ahn JJ, McGaha TL, Pahan K, Dunn SE Tags: J Immunol Source Type: research

γδ T Cell-Secreted XCL1 Mediates Anti-CD3-Induced Oral Tolerance.
In this study, we show that conventional but not plasmacytoid dendritic cells (DCs) are required for anti-CD3-induced oral tolerance. Moreover, oral anti-CD3 promotes XCL1 secretion by small intestine lamina propria γδ T cells that, in turn, induces tolerogenic XCR1+ DC migration to the mesenteric lymph node, where Treg cells are induced and oral tolerance is established. Consistent with this, TCRδ-/- mice did not develop oral tolerance upon oral administration of anti-CD3. However, XCL1 was not required for oral tolerance induced by fed Ags, indicating that a different mechanism underlies this effect. Ac...
Source: Journal of Immunology - October 2, 2019 Category: Allergy & Immunology Authors: Rezende RM, Nakagaki BN, Moreira TG, Lopes JR, Kuhn C, Tatematsu BK, Boulenouar S, Maghzi AH, Rubino S, Menezes GB, Chitnis T, Weiner HL Tags: J Immunol Source Type: research

RelB Deficiency in Dendritic Cells Protects from Autoimmune Inflammation Due to Spontaneous Accumulation of Tissue T Regulatory Cells.
In this study, we provide evidence that knockout of the relB gene in dendritic cells (DCs) of C57BL/6 mice results in a spontaneous and systemic accumulation of Foxp3+ T regulatory T cells (Tregs) partially at the expense of microbiota-reactive Tregs. Deletion of nfkb2 does not fully recapitulate this phenotype, indicating that alternative NF-κB activation via the RelB/p52 complex is not solely responsible for Treg accumulation. Deletion of RelB in DCs further results in an impaired oral tolerance induction and a marked type 2 immune bias among accumulated Foxp3+ Tregs reminiscent of a tissue Treg signature. Tissue T...
Source: Journal of Immunology - October 2, 2019 Category: Allergy & Immunology Authors: Andreas N, Potthast M, Geiselhöringer AL, Garg G, de Jong R, Riewaldt J, Russkamp D, Riemann M, Girard JP, Blank S, Kretschmer K, Schmidt-Weber C, Korn T, Weih F, Ohnmacht C Tags: J Immunol Source Type: research

Topical Adjuvant Application during Subcutaneous Vaccination Promotes Resident Memory T Cell Generation.
In this study, we evaluated the use of topical CpG oligodeoxynucleotide (ODN) as adjuvant to generate skin TRM in mice. Topical or s.c. CpG ODN adjuvant administration at the time of a s.c. Ag injection led to an accumulation of CD103- CD8 T cells in the epidermis. However, only mice with CpG ODN administered topically had significant numbers of CD103+ Ag-specific CD8 T cells persisting in the local epidermal skin, enhanced circulating memory cells in the blood, and showed protection from intradermal challenge with melanoma cells. Generation of Ag-specific CD8 T cells was dependent on TLR9 expression on hematopoietic cells...
Source: Journal of Immunology - October 2, 2019 Category: Allergy & Immunology Authors: Lai JCY, Cheng WK, Hopkins PD, Komba M, Carlow DA, Dutz JP Tags: J Immunol Source Type: research

Activation-Induced Cell Death of Mucosal-Associated Invariant T Cells Is Amplified by OX40 in Type 2 Diabetic Patients.
In this study, we demonstrate that the costimulatory TNF superfamily receptor OX40 was highly expressed in MAIT cells of patients with T2D. Compared with OX40-negative MAIT cells, OX40-positive MAIT cells showed a high activation and a memory phenotype. Surprisingly, OX40 expression was negatively correlated with the frequency of MAIT cells in the peripheral blood of T2D patients. Increased cleaved caspase-3 levels were observed in OX40+-expressing MAIT cells in T2D patients. In vitro, activated OX40 signaling by recombinant OX40L protein promoted caspase-3 activation and apoptosis of MAIT cells. Inhibition of caspase-3 re...
Source: Journal of Immunology - October 2, 2019 Category: Allergy & Immunology Authors: Zhang M, Ming S, Gong S, Liang S, Luo Y, Liang Z, Cao C, Lao J, Shang Y, Li X, Wang M, Zhong G, Xu L, Wu M, Wu Y Tags: J Immunol Source Type: research

The Tumor-Immune Response Is Not Compromised by Mesenchymal Stromal Cells in Humanized Mice.
In this study, we wanted to investigate the impact of human umbilical cord-derived MSCs (hUC-MSCs) on tumor growth in humanized mice generated by the human adoptive transfer of PBMCs or the cotransplantation of hematopoietic stem cells and human thymic tissue (human BLT [Hu-BLT]). Our results showed that the growth and immune rejection of engineered human fibroblastic tumors was not altered by the injection of hUC-MSCs in immune-deficient or humanized mice, respectively. This was observed whether tumor cells were injected s.c. or i.v. and independently of the injection route of the hUC-MSCs. Moreover, only in Hu-BLT mice d...
Source: Journal of Immunology - October 2, 2019 Category: Allergy & Immunology Authors: Moquin-Beaudry G, Colas C, Li Y, Bazin R, Guimond JV, Haddad E, Beauséjour C Tags: J Immunol Source Type: research

TNF- α Contributes to Lymphoid Tissue Disorganization and Germinal Center B Cell Suppression during Intracellular Bacterial Infection.
TNF-α Contributes to Lymphoid Tissue Disorganization and Germinal Center B Cell Suppression during Intracellular Bacterial Infection. J Immunol. 2019 Sep 30;: Authors: Popescu M, Cabrera-Martinez B, Winslow GM Abstract Bacterial, parasitic, and viral infections are well-known causes of lymphoid tissue disorganization, although the factors, both host and/or pathogen derived, that mediate these changes are largely unknown. Ehrlichia muris infection in mice causes a loss of germinal center (GC) B cells that is accompanied by the generation of extrafollicular T-bet+ CD11c+ plasmablasts and IgM memor...
Source: Journal of Immunology - September 30, 2019 Category: Allergy & Immunology Authors: Popescu M, Cabrera-Martinez B, Winslow GM Tags: J Immunol Source Type: research

TNF-Mediated Compensatory Immunity to Mycobacterium avium in the Absence of Macrophage Activation by IFN- γ.
TNF-Mediated Compensatory Immunity to Mycobacterium avium in the Absence of Macrophage Activation by IFN-γ. J Immunol. 2019 Sep 27;: Authors: Resende M, Cardoso MS, Fróis-Martins R, Borges M, Jordan MB, Castro AG, Appelberg R Abstract Granuloma formation is a hallmark of several infectious diseases, including those caused by Mycobacterium sp These structures are composed of accumulations of inflammatory cells, and it has been shown that cytokines such as IFN-γ and TNF-α are required for granuloma assembly during M. avium infections in mice. Macrophages (MΦs) insensitive to...
Source: Journal of Immunology - September 27, 2019 Category: Allergy & Immunology Authors: Resende M, Cardoso MS, Fróis-Martins R, Borges M, Jordan MB, Castro AG, Appelberg R Tags: J Immunol Source Type: research

BTLA-HVEM Checkpoint Axis Regulates Hepatic Homeostasis and Inflammation in a ConA-Induced Hepatitis Model in Zebrafish.
In this study, we explored the regulatory role of the Btla-Hvem axis in a ConA-induced hepatitis model in zebrafish. Results showed that Btla and Hvem were differentially expressed on intrahepatic Cd8+ T cells and hepatocytes. Knockdown of Btla or Hvem significantly promoted hepatic inflammation. Btla was highly expressed in Cd8+ T cells in healthy liver but was downregulated in inflamed liver, as evidenced by a disparate proportion of Cd8+Btla+ and Cd8+Btla- T cells in individuals without or with ConA stimulation. Cd8+Btla+ T cells showed minimal cytotoxicity to hepatocytes, whereas Cd8+Btla- T cells were strongly reactiv...
Source: Journal of Immunology - September 27, 2019 Category: Allergy & Immunology Authors: Shi W, Shao T, Li JY, Fan DD, Lin AF, Xiang LX, Shao JZ Tags: J Immunol Source Type: research

IFN- γ-Dependent Reduction of Erythrocyte Life Span Leads to Anemia during Mycobacterial Infection.
IFN-γ-Dependent Reduction of Erythrocyte Life Span Leads to Anemia during Mycobacterial Infection. J Immunol. 2019 Sep 27;: Authors: Gomes AC, Moreira AC, Silva T, Neves JV, Mesquita G, Almeida AA, Barreira-Silva P, Fernandes R, Resende M, Appelberg R, Rodrigues PNS, Gomes MS Abstract Anemia is a frequent and challenging complication of mycobacterial infections. We used a model of disseminated Mycobacterium avium infection in mice to investigate the mechanisms of mycobacteria-induced anemia. We found increased formation of RBC in the bone marrow and spleen of infected mice. Infection induced ret...
Source: Journal of Immunology - September 27, 2019 Category: Allergy & Immunology Authors: Gomes AC, Moreira AC, Silva T, Neves JV, Mesquita G, Almeida AA, Barreira-Silva P, Fernandes R, Resende M, Appelberg R, Rodrigues PNS, Gomes MS Tags: J Immunol Source Type: research

A Novel Caspase-1 Biosensor to Monitor the Progression of Inflammation In Vivo.
In this study, we sought to develop a biosensor that would allow us to monitor the initiation, progression, and resolution of inflammation in living animals. To this end, we inserted a known caspase-1 target sequence into a circularly permuted luciferase construct that becomes bioluminescent upon protease cleavage. This biosensor was activated in response to various inflammatory stimuli in human monocytic cell lines and murine bone marrow-derived macrophages. Next, we generated C57BL/6 transgenic mice constitutively expressing the caspase-1 biosensor. We were able to monitor the spatiotemporal dynamics of caspase-1 activat...
Source: Journal of Immunology - September 27, 2019 Category: Allergy & Immunology Authors: Talley S, Kalinina O, Winek M, Paik W, Cannon AR, Alonzo F, Choudhry MA, Knight KL, Campbell EM Tags: J Immunol Source Type: research

STAT4 Directs a Protective Innate Lymphoid Cell Response to Gastrointestinal Infection.
Abstract Innate lymphoid cells (ILCs) are strategically positioned at mucosal barrier surfaces where they respond quickly to infection or injury. Therefore, we hypothesized that ILCs are key contributors to the early immune response in the intestine against Listeria monocytogenes Using a modified strain of L. monocytogenes that mimics human gastrointestinal listeriosis in mice, we find ILCs to be essential for control of early replication of L. monocytogenes in the intestine as well as for restricted dissemination of bacteria to peripheral tissues. Specifically, group 1 ILCs (ILC1s) and group 3 ILCs (ILC3s) respon...
Source: Journal of Immunology - September 27, 2019 Category: Allergy & Immunology Authors: Dulson SJ, Watkins EE, Crossman DK, Harrington LE Tags: J Immunol Source Type: research

Immune Sensing of Aeroallergen-Associated Double-Stranded RNA Triggers an IFN Response and Modulates Type 2 Lung Inflammation.
In this study, we report that the most common aeroallergen, house dust mite (HDM), harbors a dsRNA species (HDM-dsRNA) that can activate TLR3-mediated IFN responses and counteract the development of an uncontrolled type 2 immune response. We demonstrate that the mouse strains defective in the dsRNA-sensing pathways show aggravated type 2 inflammation defined by severe eosinophilia, elevated level of type 2 cytokines, and mucus overproduction in a model of allergic lung inflammation. The inability to sense HDM-dsRNA resulted in significant increases in airway hyperreactivity. We further show that the administration of the p...
Source: Journal of Immunology - September 27, 2019 Category: Allergy & Immunology Authors: She L, Alanazi HH, Yan L, Zou Y, Sun Y, Dube PH, Brooks EG, Barrera GD, Lai Z, Chen Y, Liu Y, Zhang X, Li XD Tags: J Immunol Source Type: research

Differential Effect of Mucosal NKp44+ Innate Lymphoid Cells and Δγ Cells on Simian Immunodeficiency Virus Infection Outcome in Rhesus Macaques.
Differential Effect of Mucosal NKp44+ Innate Lymphoid Cells and Δγ Cells on Simian Immunodeficiency Virus Infection Outcome in Rhesus Macaques. J Immunol. 2019 Sep 25;: Authors: Rahman MA, Ko EJ, Enyindah-Asonye G, Helmold Hait S, Hogge C, Hunegnaw R, Venzon DJ, Hoang T, Robert-Guroff M Abstract NK cells are essential for controlling viral infections. We investigated NK cell and innate lymphoid cell (ILC) dynamics and function in rhesus macaque rectal tissue and blood following mucosal priming with replicating adenovirus (Ad)-SIV recombinants, systemic boosting with SIV envelope protein, a...
Source: Journal of Immunology - September 25, 2019 Category: Allergy & Immunology Authors: Rahman MA, Ko EJ, Enyindah-Asonye G, Helmold Hait S, Hogge C, Hunegnaw R, Venzon DJ, Hoang T, Robert-Guroff M Tags: J Immunol Source Type: research

Early KLRG1+ but Not CD57+CD8+ T Cells in Primary Cytomegalovirus Infection Predict Effector Function and Viral Control.
Abstract CMV remains an important opportunistic pathogen in high-risk lung transplant recipients. We characterized the phenotype and function of CD8+ T cells from acute/primary into chronic CMV infection in 23 (donor+/recipient-; D+R-) lung transplant recipients and found rapid induction of both KLRG1+ and/or CD57+ CMV-specific CD8+ T cells with unexpected coexpression of CD27. These cells demonstrated maturation from an acute effector T cell (TAEFF) to an effector memory T cell (TEM) phenotype with progressive enrichment of KLRG1+CD57+CD27- cells into memory. CMV-specific KLRG1+ TAEFF were capable of in vitro pro...
Source: Journal of Immunology - September 25, 2019 Category: Allergy & Immunology Authors: Hoji A, Popescu ID, Pipeling MR, Shah PD, Winters SA, McDyer JF Tags: J Immunol Source Type: research

The Deubiquitinating Enzyme Ubiquitin-Specific Peptidase 11 Potentiates TGF- β Signaling in CD4+ T Cells to Facilitate Foxp3+ Regulatory T and TH17 Cell Differentiation.
The Deubiquitinating Enzyme Ubiquitin-Specific Peptidase 11 Potentiates TGF-β Signaling in CD4+ T Cells to Facilitate Foxp3+ Regulatory T and TH17 Cell Differentiation. J Immunol. 2019 Sep 25;: Authors: Istomine R, Alvarez F, Almadani Y, Philip A, Piccirillo CA Abstract Foxp3+ regulatory T (TREG) cells are central mediators in the control of peripheral immune responses. Genome-wide transcriptional profiles show canonical signatures for Foxp3+ TREG cells, distinguishing them from Foxp3- effector T (TEFF) cells. We previously uncovered distinct mRNA translational signatures differentiating CD4+ TEF...
Source: Journal of Immunology - September 25, 2019 Category: Allergy & Immunology Authors: Istomine R, Alvarez F, Almadani Y, Philip A, Piccirillo CA Tags: J Immunol Source Type: research

Distinct PLZF+CD8 αα+ Unconventional T Cells Enriched in Liver Use a Cytotoxic Mechanism to Limit Autoimmunity.
Distinct PLZF+CD8αα+ Unconventional T Cells Enriched in Liver Use a Cytotoxic Mechanism to Limit Autoimmunity. J Immunol. 2019 Sep 25;: Authors: Sheng H, Marrero I, Maricic I, Fanchiang SS, Zhang S, Sant'Angelo DB, Kumar V Abstract Hepatic immune system is uniquely challenged to mount a controlled effector response to pathogens while maintaining tolerance to diet and microbial Ags. We have identified a novel population of innate-like, unconventional CD8αα+TCRαβ+ T cells in naive mice and in human peripheral blood, called CD8αα Tunc, capable of controlling...
Source: Journal of Immunology - September 25, 2019 Category: Allergy & Immunology Authors: Sheng H, Marrero I, Maricic I, Fanchiang SS, Zhang S, Sant'Angelo DB, Kumar V Tags: J Immunol Source Type: research

A Human IgE Antibody Binding Site on Der p 2 for the Design of a Recombinant Allergen for Immunotherapy.
acute;s A Abstract Der p 2 is one of the most important allergens from the house dust mite Dermatophagoides pteronyssinus Identification of human IgE Ab binding epitopes can be used for rational design of allergens with reduced IgE reactivity for therapy. Antigenic analysis of Der p 2 was performed by site-directed mutagenesis based on the x-ray crystal structure of the allergen in complex with a Fab from the murine IgG mAb 7A1 that binds an epitope overlapping with human IgE binding sites. Conformational changes upon Ab binding were confirmed by nuclear magnetic resonance using a 7A1-single-chain variable fragmen...
Source: Journal of Immunology - September 25, 2019 Category: Allergy & Immunology Authors: Glesner J, Kapingidza AB, Godzwon M, Offermann LR, Mueller GA, DeRose EF, Wright P, Richardson CM, Woodfolk JA, Vailes LD, Wünschmann S, London RE, Chapman MD, Ohlin M, Chruszcz M, Pomés A Tags: J Immunol Source Type: research

IL-4 and IL-17A Cooperatively Promote Hydrogen Peroxide Production, Oxidative DNA Damage, and Upregulation of Dual Oxidase 2 in Human Colon and Pancreatic Cancer Cells.
ow JH Abstract Dual oxidase 2 (DUOX2) generates H2O2 that plays a critical role in both host defense and chronic inflammation. Previously, we demonstrated that the proinflammatory mediators IFN-γ and LPS enhance expression of DUOX2 and its maturation factor DUOXA2 through STAT1- and NF-κB‒mediated signaling in human pancreatic cancer cells. Using a panel of colon and pancreatic cancer cell lines, we now report the induction of DUOX2/DUOXA2 mRNA and protein expression by the TH2 cytokine IL-4. IL-4 activated STAT6 signaling that, when silenced, significantly decreased induction of DUOX2. Furthermore, ...
Source: Journal of Immunology - September 23, 2019 Category: Allergy & Immunology Authors: Wu Y, Konaté MM, Lu J, Makhlouf H, Chuaqui R, Antony S, Meitzler JL, Difilippantonio MJ, Liu H, Juhasz A, Jiang G, Dahan I, Roy K, Doroshow JH Tags: J Immunol Source Type: research

Biased S1PR1 Signaling in B Cells Subverts Responses to Homeostatic Chemokines, Severely Disorganizing Lymphoid Organ Architecture.
In this study, we show that the B cell-specific loss of GRK2 severely disrupts B cell trafficking and immune cell homeostasis. The GRK2 deficiency in developing murine B cells leads to a severe immune phenotype, including a major reduction of bone marrow IgD+ cells, splenomegaly with a loss of white pulp and grossly expanded red pulp, a deficit of Peyer patches, and small lymph nodes with marked reductions in B cell numbers. The major phenotypes in these mice arise from excessive S1PR1 signaling combined with inadequate homeostatic chemokine receptor signaling. CXCL13 signaling is the most severely compromised. In B cells,...
Source: Journal of Immunology - September 23, 2019 Category: Allergy & Immunology Authors: Hwang IY, Park C, Harrison K, Kehrl JH Tags: J Immunol Source Type: research

In Vivo Function of the Lipid Raft Protein Flotillin-1 during CD8+ T Cell-Mediated Host Surveillance.
In this study, we analyzed morphology and migration parameters of murine wild-type and Flot1-/- CD8+ T cells using in vitro assays and intravital two-photon microscopy of lymphoid and nonlymphoid tissues. Flot1-/- CD8+ T cells displayed significant alterations in cell shape and motility parameters in vivo but showed comparable homing to lymphoid organs and intact in vitro migration to chemokines. Furthermore, their clonal expansion and infiltration into nonlymphoid tissues during primary and secondary antiviral immune responses was comparable to wild-type CD8+ T cells. Taken together, Flot1 plays a detectable but unexpecte...
Source: Journal of Immunology - September 23, 2019 Category: Allergy & Immunology Authors: Ficht X, Ruef N, Stolp B, Samson GPB, Moalli F, Page N, Merkler D, Nichols BJ, Diz-Muñoz A, Legler DF, Niggli V, Stein JV Tags: J Immunol Source Type: research

Detection of Cell Surface Ligands for Human Synovial γδ T Cells.
Detection of Cell Surface Ligands for Human Synovial γδ T Cells. J Immunol. 2019 Sep 23;: Authors: Collins C, Lui Y, Santos AM, Ballif BA, Gogerly-Moragoda AM, Brouwer H, Ross R, Balagurunathan K, Sharma S, Wright GJ, Davis S, Budd RC Abstract Lack of understanding of the nature and physiological regulation of γδ T cell ligands has considerably hampered full understanding of the function of these cells. We developed an unbiased approach to identify human γδ T cells ligands by the production of a soluble TCR-γδ (sTCR-γδ) tetramer from a synovi...
Source: Journal of Immunology - September 23, 2019 Category: Allergy & Immunology Authors: Collins C, Lui Y, Santos AM, Ballif BA, Gogerly-Moragoda AM, Brouwer H, Ross R, Balagurunathan K, Sharma S, Wright GJ, Davis S, Budd RC Tags: J Immunol Source Type: research

Rhinovirus-Induced SIRT-1 via TLR2 Regulates Subsequent Type I and Type III IFN Responses in Airway Epithelial Cells.
In this study, we show that in normal cells, TLR2 limits RV-induced IFN responses by attenuating STAT1 and STAT2 phosphorylation and this was associated with TLR2-dependent SIRT-1 expression. Further, inhibition of SIRT-1 enhanced RV-induced IFN responses, and this was accompanied by increased STAT1/STAT2 phosphorylation, indicating that TLR2 may limit RV-induced IFN responses via SIRT-1. COPD airway epithelial cells showed attenuated IL-8 responses to TLR2 agonist despite expressing TLR2 similar to normal, indicating dysregulation in TLR2 signaling pathway. Unlike normal, COPD cells failed to show RV-induced TLR2-dependen...
Source: Journal of Immunology - September 23, 2019 Category: Allergy & Immunology Authors: Xander N, Reddy Vari H, Eskandar R, Li W, Bolla S, Marchetti N, Sajjan US Tags: J Immunol Source Type: research

Mycobacterium tuberculosis-Induced Bronchoalveolar Lavage Gene Expression Signature in Latent Tuberculosis Infection Is Dominated by Pleiotropic Effects of CD4+ T Cell-Dependent IFN- γ Production despite the Presence of Polyfunctional T Cells within the Airways.
In this study, we evaluated global M. tuberculosis-induced gene expression in airway immune cells obtained by bronchoalveolar lavage (BAL) of individuals with latent TB infection (LTBI) and M. tuberculosis-naive controls. In prior studies, we demonstrated that BAL cells from LTBI individuals display substantial enrichment for M. tuberculosis-responsive CD4+ T cells compared with matched peripheral blood samples. We therefore specifically assessed the impact of the depletion of CD4+ and CD8+ T cells on M. tuberculosis-induced BAL cell gene expression in LTBI. Our studies identified 12 canonical pathways and a 47-gene signat...
Source: Journal of Immunology - September 20, 2019 Category: Allergy & Immunology Authors: Jarvela J, Moyer M, Leahy P, Bonfield T, Fletcher D, Mkono WN, Aung H, Canaday DH, Dazard JE, Silver RF Tags: J Immunol Source Type: research

Identification of a Novel Role for Foxo3 Isoform2 in Osteoclastic Inhibition.
In this study, we established a conditional allele of Foxo3 in mice that deletes the full-length Foxo3 except isoform2, a close ortholog of the human FOXO3 isoform2. Expression of Foxo3 isoform2 specifically in macrophage/osteoclast lineage suppresses osteoclastogenesis and leads to the osteopetrotic phenotype in mice. Mechanistically, Foxo3 isoform2 enhances the expression of type I IFN response genes to RANKL stimulation and thus inhibits osteoclastogenesis via endogenous IFN-β-mediated feedback inhibition. Our findings identify, to our knowledge, the first known biological function of Foxo3 isoform2 that acts as a ...
Source: Journal of Immunology - September 20, 2019 Category: Allergy & Immunology Authors: Xu C, Vitone GJ, Inoue K, Ng C, Zhao B Tags: J Immunol Source Type: research

Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated with Fibrosis.
In this study, we examined whether RMϕs capable of inhibiting inflammatory responses of CAMϕs could also inhibit AAMϕs and their profibrotic responses. Our results demonstrated that RMϕs significantly dampened the alternate activation phenotype of AAMϕs generated in vitro and intrinsically occurring AAMϕs from TACI-/- macrophages. Further, RMϕs inhibited AAMϕ-promoted arginase activity and fibroblast proliferation in vitro. This inhibition occurred regardless of the strength, duration, and mode of alternative activation and was only partially dependent on IL-10. In the chlorhexidine gluconate-induced peritoneal fib...
Source: Journal of Immunology - September 20, 2019 Category: Allergy & Immunology Authors: Chandrasekaran P, Izadjoo S, Stimely J, Palaniyandi S, Zhu X, Tafuri W, Mosser DM Tags: J Immunol Source Type: research

T Cell-Specific Adaptor Protein Regulates Mitochondrial Function and CD4+ T Regulatory Cell Activity In Vivo following Transplantation.
Abstract The T cell-specific adaptor protein (TSAd), encoded by the SH2D2A gene, is an intracellular molecule that binds Lck to elicit signals that result in cytokine production in CD4+ T effector cells (Teff). Nevertheless, using Sh2d2a knockout (KO; also called TSAd-/-) mice, we find that alloimmune CD4+ Teff responses are fully competent in vivo. Furthermore, and contrary to expectations, we find that allograft rejection is accelerated in KO recipients of MHC class II-mismatched B6.C-H-2bm12 heart transplants versus wild-type (WT) recipients. Also, KO recipients of fully MHC-mismatched cardiac allografts are re...
Source: Journal of Immunology - September 20, 2019 Category: Allergy & Immunology Authors: Wedel J, Stack MP, Seto T, Sheehan MM, Flynn EA, Stillman IE, Kong SW, Liu K, Briscoe DM Tags: J Immunol Source Type: research

Cutting Edge: ROR1/CD19 Receptor Complex Promotes Growth of Mantle Cell Lymphoma Cells Independently of the B Cell Receptor-BTK Signaling Pathway.
This study demonstrates that ROR1/CD19 complex effectively substitutes for BCR-BTK signaling to promote activation and growth of MCL cells. Therefore, ROR1 expression and activation may represent a novel mechanism of resistance to inhibition of BCR/BTK signaling in MCL. Our results provide a rationale to screen MCL patients for ROR1 expression and to consider new therapies targeting ROR1 and/or CD19 or their downstream signaling pathways for MCL-expressing ROR1. PMID: 31534006 [PubMed - as supplied by publisher] (Source: Journal of Immunology)
Source: Journal of Immunology - September 18, 2019 Category: Allergy & Immunology Authors: Zhang Q, Wang HY, Liu X, Nunez-Cruz S, Jillab M, Melnikov O, Nath K, Glickson J, Wasik MA Tags: J Immunol Source Type: research

Involvement of GPx4-Regulated Lipid Peroxidation in Idiopathic Pulmonary Fibrosis Pathogenesis.
In this study, we sought to examine the involvement of GPx4-modulated lipid peroxidation in regulating TGF-β-induced myofibroblast differentiation. Bleomycin-induced lung fibrosis development in mouse models with genetic manipulation of GPx4 were examined. Immunohistochemical evaluations for GPx4 and lipid peroxidation were performed in IPF lung tissues. Immunohistochemical evaluations showed reduced GPx4 expression levels accompanied by increased 4-hydroxy-2-nonenal in fibroblastic focus in IPF lungs. TGF-β-induced myofibroblast differentiation was enhanced by GPx4 knockdown with concomitantly enhanced lipid per...
Source: Journal of Immunology - September 18, 2019 Category: Allergy & Immunology Authors: Tsubouchi K, Araya J, Yoshida M, Sakamoto T, Koumura T, Minagawa S, Hara H, Hosaka Y, Ichikawa A, Saito N, Kadota T, Kurita Y, Kobayashi K, Ito S, Fujita Y, Utsumi H, Hashimoto M, Wakui H, Numata T, Kaneko Y, Mori S, Asano H, Matsudaira H, Ohtsuka T, Naka Tags: J Immunol Source Type: research

Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling.
In this study, we identified that deubiquitinase USP27X could interact with cGAS and cleave K48-linked polyubiquitination chains from cGAS, leading to cGAS stabilization. Consistently, knockout of Usp27x in mice macrophages resulted in an accelerated turnover of cGAS, decreased cGAMP production, phosphorylation of TBK1 and IRF3, and IFN-β production. Furthermore, Usp27x knockout mice macrophages showed impaired innate antiviral responses against HSV type 1 infection. Our data suggest that USP27X is a novel regulator of the cGAS-STING cytosolic DNA sensing pathway. PMID: 31534008 [PubMed - as supplied by publisher...
Source: Journal of Immunology - September 18, 2019 Category: Allergy & Immunology Authors: Guo Y, Jiang F, Kong L, Li B, Yang Y, Zhang L, Liu B, Zheng Y, Gao C Tags: J Immunol Source Type: research

Cross-Reactive Antigen Expressed by B6 Splenocytes Drives Receptor Editing and Marginal Zone Differentiation of IgG2a-Reactive AM14 V κ8 B Cells.
Cross-Reactive Antigen Expressed by B6 Splenocytes Drives Receptor Editing and Marginal Zone Differentiation of IgG2a-Reactive AM14 Vκ8 B Cells. J Immunol. 2019 Sep 18;: Authors: Nündel K, Mande P, Moses SL, Busto P, Cullen JL, Schmidt MR, Shlomchik MJ, Woodland RT, Marshak-Rothstein A Abstract The AM14 BCR, derived from an autoimmune MRL/lpr mouse, binds autologous IgG2aa/j with low affinity, and as a result, AM14 B cells only proliferate in response to IgG2a immune complexes that incorporate DNA, RNA, or nucleic acid-binding proteins that serve as autoadjuvants. As such, AM14 B cells have...
Source: Journal of Immunology - September 18, 2019 Category: Allergy & Immunology Authors: Nündel K, Mande P, Moses SL, Busto P, Cullen JL, Schmidt MR, Shlomchik MJ, Woodland RT, Marshak-Rothstein A Tags: J Immunol Source Type: research

Intra- and Extracellular Degradation of Neutrophil Extracellular Traps by Macrophages and Dendritic Cells.
In this study, we investigated the interaction of NETs released by freshly isolated, PMA-stimulated primary human neutrophils with primary human monocyte-derived macrophages or dendritic cells (DCs). NETs were internalized by macrophages, and removal of the protein component prevented engulfment of NETs, whereas complexation with LL-37 restored the uptake of "naked" (protein-free) NETs. NETs were also found to dampen the bacterial LPS-induced maturation of DCs. Cytokine profiling was conducted by using a multiplex array following the interaction of NETs with macrophages or DCs, and NETs alone were found to be non...
Source: Journal of Immunology - September 13, 2019 Category: Allergy & Immunology Authors: Lazzaretto B, Fadeel B Tags: J Immunol Source Type: research

IL-37 Attenuates Lung Fibrosis by Inducing Autophagy and Regulating TGF- β1 Production in Mice.
In this study, we found that the IL-37 protein was expressed in alveolar epithelial cells (AECs) and alveolar macrophages in healthy controls but significantly reduced in patients with IPF. IL-37 significantly inhibited oxidative stress-induced primary mouse AEC death in a dose-dependent manner, and knockdown of IL-37 significantly potentiated human lung cancer-derived AEC (A549 cells) death. IL-37 attenuated constitutive mRNA and protein expression of fibronectin and collagen I in primary human lung fibroblasts. IL-37 inhibited TGF-β1-induced lung fibroblast proliferation and downregulated the TGF-β1 signaling p...
Source: Journal of Immunology - September 13, 2019 Category: Allergy & Immunology Authors: Kim MS, Baek AR, Lee JH, Jang AS, Kim DJ, Chin SS, Park SW Tags: J Immunol Source Type: research

Terminal Effector CD8 T Cells Defined by an IKZF2+IL-7R- Transcriptional Signature Express Fc γRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity.
In this study, we investigated whether such CD8 T cell populations can perform unconventional innate-like antiviral effector functions. Chronic untreated HIV-1 infection was associated with elevated numbers of CD45RA+CD57+ terminal effector CD8 T cells expressing FcγRIIIA (CD16). The FcγRIIIA+ CD8 T cells displayed a distinctive transcriptional profile between conventional CD8 T cells and NK cells, characterized by high levels of IKZF2 and low expression of IL7R This transcriptional profile translated into a distinct NKp80+ IL-7Rα- surface phenotype with high expression of the Helios transcription factor....
Source: Journal of Immunology - September 13, 2019 Category: Allergy & Immunology Authors: Naluyima P, Lal KG, Costanzo MC, Kijak GH, Gonzalez VD, Blom K, Eller LA, Creegan M, Hong T, Kim D, Quinn TC, Björkström NK, Ljunggren HG, Serwadda D, Katabira ET, Sewankambo NK, Gray RH, Baeten JM, Michael NL, Wabwire-Mangen F, Robb ML, Bolton DL, Sand Tags: J Immunol Source Type: research

A Hint of Primitive Mucosal Immunity in Shrimp through Marsupenaeus japonicus Gill C-Type Lectin.
Abstract Lectins are found in most living organisms, providing immune surveillance by binding to carbohydrate ligands. In fishes, C-type lectins were isolated from mucus of respiratory organs (skin and gills), where they aid the mucosal immune response in regulating microbiota and suppressing pathogens. In shrimp, however, no mucosal immunity or any form of gill-specific immune defense has been reported, and most identified C-type lectins are associated with hemocyte cellular and humoral responses. Interestingly, our microarray analysis revealed the localization of highly expressed novel biodefense genes in gills,...
Source: Journal of Immunology - September 13, 2019 Category: Allergy & Immunology Authors: Alenton RRR, Koiwai K, Nakamura R, Thawonsuwan J, Kondo H, Hirono I Tags: J Immunol Source Type: research

KIR Polymorphism Modulates the Size of the Adaptive NK Cell Pool in Human Cytomegalovirus-Infected Individuals.
In this study, the role of KIR polymorphism and expression in this process was analyzed. It is shown that strong NKG2C+ NK cell expansions are dominated by single KIR clones, whereas moderate expansions are frequently polyclonal (p
Source: Journal of Immunology - September 13, 2019 Category: Allergy & Immunology Authors: Manser AR, Scherenschlich N, Thöns C, Hengel H, Timm J, Uhrberg M Tags: J Immunol Source Type: research

Progranulin Decreases Susceptibility to Streptococcus pneumoniae in Influenza and Protects against Lethal Coinfection.
Abstract Streptococcus pneumoniae coinfection is a major cause of mortality in influenza pandemics. Growing evidence shows that uncontrolled immune response results in severe tissue damage and thereby promotes death in coinfection. Progranulin (PGRN) is widely expressed in immune and epithelial cells and exerts anti-inflammatory role in many diseases. We found that PGRN levels were significantly elevated in clinical influenza/S. pneumoniae-coinfected patients. C57BL/6 wild-type (WT) and PGRN-deficient (PGRN-/-) mice were infected with influenza virus PR8 and then superchallenged with S. pneumoniae serotype 19F. Co...
Source: Journal of Immunology - September 13, 2019 Category: Allergy & Immunology Authors: Wang X, Yuan J, Wang H, Gan N, Zhang Q, Liu B, Wang J, Shu Z, Rao L, Gou X, Zhang H, Yin Y, Zhang X Tags: J Immunol Source Type: research

Lymphatic Cannulation for Lymph Sampling and Molecular Delivery.
In this study, we describe a protocol for cannulation of mouse and rat lymphatic collectors that is suitable for the following: the "omic" sampling of pre- and postnodal lymph, collected from different anatomical districts; the phenotyping of immune cells circulating between parenchymal organs and draining lymph nodes; injection of known amounts of molecules for quantitative immunological studies of nodal trafficking and/or clearance; and monitoring an organ's biochemical omic changes in pathological conditions. Our data indicate that probing the lymphatic fluid can provide an accurate snapshot of an organ's phys...
Source: Journal of Immunology - September 13, 2019 Category: Allergy & Immunology Authors: Zawieja DC, Thangaswamy S, Wang W, Furtado R, Clement CC, Papadopoulos Z, Vigano M, Bridenbaugh EA, Zolla L, Gashev AA, Kipnis J, Lauvau G, Santambrogio L Tags: J Immunol Source Type: research

CD24hiCD38hi and CD24hiCD27+ Human Regulatory B Cells Display Common and Distinct Functional Characteristics.
In this study, we report that the frequency of IL-10-producing Bregs in human peripheral blood, spleens, and tonsils is similar, but they display heterogenous surface phenotypes. Nonetheless, CD24hiCD38hi transitional B cells (TBs) and CD24hiCD27+ B cells (human equivalent of murine B10 cells) are the major IL-10-producing B cells. They both suppress CD4+ T cell proliferation as well as IFN-γ/IL-17 expression. However, CD24hiCD27+ B cells were more efficient than TBs at suppressing CD4+ T cell proliferation and IFN-γ/IL-17 expression, whereas they both coexpress IL-10 and TNF-α. TGF-β1 and granzyme B...
Source: Journal of Immunology - September 11, 2019 Category: Allergy & Immunology Authors: Hasan MM, Thompson-Snipes L, Klintmalm G, Demetris AJ, O'Leary J, Oh S, Joo H Tags: J Immunol Source Type: research

Helicobacter pylori Exploits the NLRC4 Inflammasome to Dampen Host Defenses.
In this study, we analyzed the role of the NLRC4 inflammasome during H. pylori infection. Our results indicate that NLRC4 and a functional type IV secretion system are crucial for the production of IL-18 from human and murine gastric epithelial cells. In vivo, Nlrc4-/- mice failed to produce gastric IL-18 upon H. pylori infection. Compared with wild type mice, Nlrc4-/- mice controlled H. pylori better without showing strong inflammation. Moreover, H. pylori-induced IL-18 inhibits β-defensin 1 expression in a NF-κB-dependent manner, resulting in higher bacterial colonization. At the same time, inflammasome activa...
Source: Journal of Immunology - September 11, 2019 Category: Allergy & Immunology Authors: Semper RP, Vieth M, Gerhard M, Mejías-Luque R Tags: J Immunol Source Type: research