Publisher: American Assoc of Immunologists   (Total: 2 journals)   [Sort by number of followers]

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J. of Immunology     Full-text available via subscription   (Followers: 67, SJR: 2.837, CiteScore: 5)
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Journal of Immunology
Journal Prestige (SJR): 2.837
Citation Impact (citeScore): 5
Number of Followers: 67  
 
  Full-text available via subscription Subscription journal
ISSN (Print) 0022-1767 - ISSN (Online) 1550-6606
Published by American Assoc of Immunologists Homepage  [2 journals]
  • The All-Encompassing Importance of Innate Immunity [PRESIDENT'S ADDRESS]

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      Authors: Ting; J. P.- Y.
      Pages: 2445 - 2449
      Abstract: In their AAI President’s Addresses reproduced in this issue, Jeremy M. Boss, Ph.D. (AAI ’94; AAI President 2019–2020) and Jenny P.-Y. Ting, Ph.D. (AAI ’97; AAI President 2020–2021) welcomed attendees to the AAI annual meeting, Virtual IMMUNOLOGY2021™. Due to the SARS-CoV-2 pandemic and the cancellation of IMMUNOLOGY2020™, Dr. Boss and Dr. Ting each presented their respective President’s Address to open the meeting.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2290008
      Issue No: Vol. 208, No. 11 (2022)
       
  • The Regulation of Immunity [PRESIDENT'S ADDRESS]

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      Authors: Boss; J. M.
      Pages: 2450 - 2455
      Abstract: In their AAI President's Addresses reproduced in this issue, Jeremy M. Boss, Ph.D. (AAI '94; AAI president 2019–2020), and Jenny P.-Y. Ting, Ph.D. (AAI '97; AAI president 2020–2021), welcomed attendees to the AAI annual meeting, Virtual IMMUNOLOGY2021™. Due to the SARS-CoV-2 pandemic and the cancellation of IMMUNOLOGY2020™, Dr. Boss and Dr. Ting each presented their respective president's address to open the meeting.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2290007
      Issue No: Vol. 208, No. 11 (2022)
       
  • Top Reads [TOP READS]

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      Pages: 2457 - 2457
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2290009
      Issue No: Vol. 208, No. 11 (2022)
       
  • CCR5: The Receptor That Unlocks the Door for HIV Entry into Cells [PILLARS
           OF IMMUNOLOGY]

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      Authors: Unutmaz; D.
      Pages: 2459 - 2460
      Abstract: This Pillars of Immunology article is a commentary on "Identification of a major co-receptor for primary isolates of HIV-1," a pivotal article written by H. Deng, R. Liu, W. Ellmeier, S. Choe, D. Unutmaz, M. Burkhart, P. Di Marzio, S. Marmon, R. E. Sutton, C. M. Hill, et al., and published in Nature, in 1996. https://www.nature.com/articles/381661a0.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2200108
      Issue No: Vol. 208, No. 11 (2022)
       
  • Cutting Edge: T Cell Responses to B.1.1.529 (Omicron) SARS-CoV-2 Variant
           Induced by COVID-19 Infection and/or mRNA Vaccination Are Largely
           Preserved [CUTTING EDGE]

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      Authors: Jergovic, M; Coplen, C. P, Uhrlaub, J. L, Beitel, S. C, Burgess, J. L, Lutrick, K, Ellingson, K. D, Watanabe, M, Nikolich-Zugich, J.
      Pages: 2461 - 2465
      Abstract: Several studies have demonstrated that the SARS-CoV-2 variant-of-concern B.1.1.529 (Omicron) exhibits a high degree of escape from Ab neutralization. Therefore, it is critical to determine how well the second line of adaptive immunity, T cell memory, performs against Omicron. To this purpose, we analyzed a human cohort (n = 327 subjects) of two- or three-dose mRNA vaccine recipients and COVID-19 postinfection subjects. We report that T cell responses against Omicron were largely preserved. IFN-–producing T cell responses remained equivalent to the response against the ancestral strain (WA1/2020), with some (~20%) loss in IL-2 single or IL-2+IFN-+ polyfunctional responses. Three-dose vaccinated participants had similar responses to Omicron relative to post–COVID-19 participants and exhibited responses significantly higher than those receiving two mRNA vaccine doses. These results provide further evidence that a three-dose vaccine regimen benefits the induction of optimal functional T cell immune memory.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2200175
      Issue No: Vol. 208, No. 11 (2022)
       
  • Restoration of Follicular T Regulatory/Helper Cell Balance by OX40L-JAG1
           Cotreatment Suppresses Lupus Nephritis in NZBWF1/j Mice [AUTOIMMUNITY]

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      Authors: Kumar, P; Balakrishnan, S, Surendra Lele, S, Setty, S, Dhingra, S, Epstein, A. L, Prabhakar, B. S.
      Pages: 2467 - 2481
      Abstract: Class-switched antinuclear autoantibodies produced by T follicular helper (TFH) cell–dependent germinal center (GC) B cell response play an essential pathogenic role in lupus nephritis (LN). The role of T follicular regulatory (TFR) cells, an effector subset of CD4+Foxp3+ T regulatory cells (Tregs), which are specialized in suppressing TFH-GC response and Ab production, remains elusive in LN. Contrasting reports have shown increased/reduced circulating TFR cells in human lupus that might not accurately reflect their presence in the GCs of relevant lymphoid organs. In this study, we report a progressive reduction in TFR cells and decreased TFR/TFH ratio despite increased Tregs in the renal lymph nodes of NZBWF1/j mice, which correlated with increased GC-B cells and proteinuria onset. Cotreatment with soluble OX40L and Jagged-1 (JAG1) proteins increased Tregs, TFR cells, and TFR/TFH ratio, with a concomitant reduction in TFH cells, GC B cells, and anti-dsDNA IgG Ab levels, and suppressed LN onset. Mechanistic studies showed attenuated TFH functions and diminished GC events such as somatic hypermutation and isotype class-switching in OX40L-JAG1–treated mice. RNA sequencing studies revealed inhibition of hypoxia-inducible factor 1-α (HIF-1a) and STAT3 signaling in T conventional cells from OX40L-JAG1–treated mice, which are critical for the glycolytic flux and differentiation into TFH cell lineage. Therefore, the increased TFR/TFH ratio seen in OX40L-JAG1–treated mice could involve both impaired differentiation of TFH cells from T conventional cells and expansion of TFR cells. We show a key role for GC-TFR/TFH imbalance in LN pathogenesis and how restoring homeostatic balance can suppress LN.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2200057
      Issue No: Vol. 208, No. 11 (2022)
       
  • Analysis of Complement Gene Expression, Clinical Associations, and
           Biodistribution of Complement Proteins in the Synovium of Early Rheumatoid
           Arthritis Patients Reveals Unique Pathophysiologic Features [CLINICAL AND
           HUMAN IMMUNOLOGY]

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      Authors: Banda, N. K; Deane, K. D, Bemis, E. A, Strickland, C, Seifert, J, Jordan, K, Goldman, K, Morgan, B. P, Moreland, L. W, Lewis, M. J, Pitzalis, C, Holers, V. M.
      Pages: 2482 - 2496
      Abstract: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and inflammation. The finding of autoantibodies in seropositive RA suggests that complement system activation might play a pathophysiologic role due to the local presence of immune complexes in the joints. Our first objective was to explore the Pathobiology of Early Arthritis Cohort (PEAC) mRNA sequencing data for correlations between clinical disease severity as measured by DAS28-ESR (disease activity score in 28 joints for erythrocyte sedimentation rate) and complement system gene expression, both in the synovium and in blood. Our second objective was to determine the biodistribution using multiplex immunohistochemical staining of specific complement activation proteins and inhibitors from subjects in the Accelerating Medicines Partnership (AMP) RA/SLE study. In the PEAC study, there were significant positive correlations between specific complement gene mRNA expression levels in the synovium and DAS28-ESR for the following complement genes: C2, FCN1, FCN3, CFB, CFP, C3AR1, C5AR1, and CR1. Additionally, there were significant negative correlations between DAS28-ESR and Colec12, C5, C6, MASP-1, CFH, and MCP. In the synovium there were also significant positive correlations between DAS28-ESR and FcR1A, FcR1B, FcR2A, and FcR3A. Notably, CFHR4 synovial expression was positively correlated following treatment with the DAS28-ESR at 6 mo, suggesting a role in worse therapeutic responses. The inverse correlation of C5 RNA expression in the synovium may underlie the failure of significant benefit from C5/C5aR inhibitors in clinical trials performed in patients with RA. Multiplex immunohistochemical analyses of early RA synovium reveal significant evidence of regional alterations of activation and inhibitory factors that likely promote local complement activation.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2101170
      Issue No: Vol. 208, No. 11 (2022)
       
  • Naturally Occurring Anti-Idiotypic Antibodies Portray a Largely Private
           Repertoire in Immune-Mediated Thrombotic Thrombocytopenic Purpura [IMMUNE
           REGULATION]

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      Authors: Heeb, S. R; Schaller, M, Kremer Hovinga, J. A.
      Pages: 2497 - 2507
      Abstract: Rare immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening disease resulting from a severe autoantibody-mediated ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13) deficiency. Acute iTTP episodes are medical emergencies, but when treated appropriately>95% of patients survive. However, at least half of survivors will eventually experience a relapse. How remission of an initial episode is achieved and factors contributing to reemergence of anti-ADAMTS13 Abs and a relapsing course are poorly understood. In acquired hemophilia and systemic lupus erythematosus, anti-idiotypic Abs counteracting and neutralizing pathogenic autoantibodies contribute to remission. We selected and amplified the splenic anti-idiotypic IgG1 Fab / repertoire of two relapsing iTTP patients on previously generated monoclonal inhibitory anti-ADAMTS13 Fabs by phage display to explore whether anti-idiotypic Abs have a role in iTTP. We obtained 27 single anti-idiotypic Fab clones, half of which had unique sequences, although both patients shared four H chain V region genes (VH1-69*01, VH3-15*01, VH3-23*01, and VH3-49*03). Anti-idiotypic Fab pools of both patients fully neutralized the inhibitor capacity of the monoclonal anti-ADAMTS13 Abs used for their selection. Preincubation of plasma samples of 22 unrelated iTTP patients stratified according to functional ADAMTS13 inhibitor titers (>2 Bethesda units/ml, or 1–2 Bethesda units/ml), with anti-idiotypic Fab pools neutralized functional ADAMTS13 inhibitors and restored ADAMTS13 activity in 18–45% of those cases. Taken together, we present evidence for the presence of an anti-idiotypic immune response in iTTP patients. The interindividual generalizability of this response is limited despite relatively uniform pathogenic anti-ADAMTS13 Abs recognizing a dominant epitope in the ADAMTS13 spacer domain.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2100868
      Issue No: Vol. 208, No. 11 (2022)
       
  • Genome-Wide Mapping of Plasma IgG N-Glycan Quantitative Trait Loci
           Identifies a Potentially Causal Association between IgG N-Glycans and
           Rheumatoid Arthritis [IMMUNOGENETICS]

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      Authors: Liu, D; Dong, J, Zhang, J, Xu, X, Tian, Q, Meng, X, Wu, L, Zheng, D, Chu, X, Wang, W, Meng, Q, Wang, Y.
      Pages: 2508 - 2514
      Abstract: Observational studies highlight associations of IgG N-glycosylation with rheumatoid arthritis (RA); however, the causality between these conditions remains to be determined. Standard and multivariable two-sample Mendelian randomization (MR) analyses integrating a summary genome-wide association study for RA and IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) data were performed to explore the potentially causal associations of IgG N-glycosylation with RA. After correcting for multiple testing (p < 2 x 10–3), the standard MR analysis based on the inverse-variance weighted method showed a significant association of genetically instrumented IgG N-glycan (GP4) with RA (odds ratioGP4 = 0.906, 95% confidence interval = 0.857–0.958, p = 5.246 x 10–4). In addition, we identified seven significant associations of genetically instrumented IgG N-glycans with RA by multivariable MR analysis (p < 2 x 10–3). Results were broadly consistent in sensitivity analyses using MR_Lasso, MR_weighted median, MR_Egger regression, and leave-one-out analysis with different instruments (all p values 0.05). In conclusion, our MR analysis incorporating genome-wide association studies and IgG N-glycan-QTL data revealed that IgG N-glycans were potentially causally associated with RA. Our findings shed light on the role of IgG N-glycosylation in the development of RA. Future studies are needed to validate our findings and to explore the underlying physiological mechanisms in the etiology of RA.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2100080
      Issue No: Vol. 208, No. 11 (2022)
       
  • Activation of CD4+ T Cell-Derived Cannabinoid Receptor 2 Signaling
           Exacerbates Sepsis via Inhibiting IL-10 [INFECTIOUS DISEASE AND HOST
           RESPONSE]

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      Authors: Chen, J; Wang, F, Zhang, S, Lin, Q, Xu, H, Zhu, T, Peng, L, Cen, F, Li, F, Wang, Z, Feng, C. G, Yin, Z, Liu, Y, Zhang, G.
      Pages: 2515 - 2522
      Abstract: The cannabinoid receptor 2 (CB2) is a receptor mainly expressed in immune cells and believed to be immunosuppressive in infective or inflammatory models. However, its role in sepsis has not been fully elucidated. In this study, we delineate the function and mechanism of CB2 in the cecal ligation and puncture–induced septic model in mice. The activation of CB2 signaling with HU308 led to decreased survival rates and more severe lung injury in septic mice, and lower IL-10 levels in peritoneal lavage fluid were observed in the CB2 agonist group. The mice with conditional knockout of CB2-encoding gene CNR2 in CD4+ T cells (CD4 Cre CNR2fl/fl) improved survival, enhanced IL-10 production, and ameliorated pulmonary damage in the sepsis model after CB2 activation. In addition, double-knockout of the CNR2 gene (Lyz2 Cre CD4 Cre CNR2fl/fl) decreased the susceptibility to sepsis compared with Lyz2 Cre CNR2fl/fl mice. Mechanistically, the blockade of IL-10 with the anti–IL-10 Ab abolished its protection in CD4 Cre CNR2fl/fl mice. In accordance with the animal study, in vitro results revealed that the lack of CNR2 in CD4+ cells elevated IL-10 production, and CB2 activation inhibited CD4+ T cell–derived IL-10 production. Furthermore, in the clinical environment, septic patients expressed enhanced CB2 mRNA levels compared with healthy donors in PBMCs, and their CB2 expression was inversely correlated with IL-10. These results suggested that the activation of CD4+ T cell–derived CB2 increased susceptibility to sepsis through inhibiting IL-10 production.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2101015
      Issue No: Vol. 208, No. 11 (2022)
       
  • Dietary Cholesterol Causes Inflammatory Imbalance and Exacerbates
           Morbidity in Mice Infected with Influenza A Virus [INFECTIOUS DISEASE AND
           HOST RESPONSE]

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      Authors: Louie, A. Y; Tingling, J, Dray, E, Hussain, J, McKim, D. B, Swanson, K. S, Steelman, A. J.
      Pages: 2523 - 2539
      Abstract: Influenza is a common cause of pneumonia-induced hospitalization and death, but how host factors function to influence disease susceptibility or severity has not been fully elucidated. Cellular cholesterol levels may affect the pathogenesis of influenza infection, as cholesterol is crucial for viral entry and replication, as well as immune cell proliferation and function. However, there is still conflicting evidence on the extent to which dietary cholesterol influences cholesterol metabolism. In this study, we examined the effects of a high-cholesterol diet in modulating the immune response to influenza A virus (IAV) infection in mice. Mice were fed a standard or a high-cholesterol diet for 5 wk before inoculation with mouse-adapted human IAV (Puerto Rico/8/1934), and tissues were collected at days 0, 4, 8, and 16 postinfection. Cholesterol-fed mice exhibited dyslipidemia characterized by increased levels of total serum cholesterol prior to infection and decreased triglycerides postinfection. Cholesterol-fed mice also displayed increased morbidity compared with control-fed mice, which was neither a result of immunosuppression nor changes in viral load. Instead, transcriptomic analysis of the lungs revealed that dietary cholesterol caused upregulation of genes involved in viral-response pathways and leukocyte trafficking, which coincided with increased numbers of cytokine-producing CD4+ and CD8+ T cells and infiltrating dendritic cells. Morbidity as determined by percent weight loss was highly correlated with numbers of cytokine-producing CD4+ and CD8+ T cells as well as granulocytes. Taken together, dietary cholesterol promoted IAV morbidity via exaggerated cellular immune responses that were independent of viral load.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2100927
      Issue No: Vol. 208, No. 11 (2022)
       
  • Translationally Controlled Tumor Protein-Mediated Stabilization of Host
           Antiapoptotic Protein MCL-1 Is Critical for Establishment of Infection by
           Intramacrophage Parasite Leishmania donovani [INFECTIOUS DISEASE AND HOST
           RESPONSE]

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      Authors: Giri, J; Basu, M, Roy, S, Mishra, T, Jana, K, Chande, A, Ukil, A.
      Pages: 2540 - 2548
      Abstract: In the early phase of infection, the intramacrophage pathogen Leishmania donovani protects its niche with the help of the antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Whether Leishmania could exploit MCL-1, an extremely labile protein, at the late phase is still unclear. A steady translational level of MCL-1 observed up to 48 h postinfection and increased caspase-3 activity in MCL-1–silenced infected macrophages documented its importance in the late hours of infection. The transcript level of MCL-1 showed a sharp decline at 6 h postinfection, and persistent MCL-1 expression in cyclohexamide-treated cells negates the possibility of de novo protein synthesis, thereby suggesting infection-induced stability. Increased ubiquitination, a prerequisite for proteasomal degradation of MCL-1, was also found to be absent in the late hours of infection. Lack of interaction with its specific E3 ubiquitin ligase MULE (MCL-1 ubiquitin ligase E3) and specific deubiquitinase USP9X prompted us to search for blockade of the ubiquitin-binding site in MCL-1. To this end, TCTP (translationally controlled tumor protein), a well-known binding partner of MCL-1 and antiapoptotic regulator, was found to be strongly associated with MCL-1 during infection. Phosphorylation of TCTP, a requirement for MCL-1 binding, was also increased in infected macrophages. Knockdown of TCTP decreased MCL-1 expression and short hairpin RNA–mediated silencing of TCTP in an infected mouse model of visceral leishmaniasis showed decreased parasite burden and induction of liver cell apoptosis. Collectively, our investigation revealed a key mechanism of how L. donovani exploits TCTP to establish infection within the host.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2100748
      Issue No: Vol. 208, No. 11 (2022)
       
  • Cyclooxygenase-Derived Prostaglandin E2 Drives IL-1-Independent
           Mycobacterium bovis Bacille Calmette-Guerin-Triggered Skin Dendritic Cell
           Migration to Draining Lymph Node [INFECTIOUS DISEASE AND HOST RESPONSE]

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      Authors: Krmeska, V; Aggio, J. B, Nylen, S, Wowk, P. F, Rothfuchs, A. G.
      Pages: 2549 - 2557
      Abstract: Inoculation of Mycobacterium bovis Bacille Calmette-Guérin (BCG) in the skin mobilizes local dendritic cells (DC) to the draining lymph node (dLN) in a process that remains incompletely understood. In this study, a mouse model of BCG skin infection was used to investigate mechanisms of skin DC migration to dLNs. We found enhanced transcription of cyclooxygenase (COX)-2 and production of COX-derived PGE2 early after BCG infection in skin. Animals treated with antagonists for COX or the PGE2 receptors EP2 and EP4 displayed a marked reduction in the entry of skin DCs and BCG to dLNs, uncovering an important contribution of COX-derived PGE2 in this migration process. In addition, live BCG bacilli were needed to invoke DC migration through this COX-PGE2 pathway. Having previously shown that IL-1R partially regulates BCG-induced relocation of skin DCs to dLNs, we investigated whether PGE2 release was under control of IL-1. Interestingly, IL-1R ligands IL-1α/β were not required for early transcription of COX-2 or production of PGE2 in BCG-infected skin, suggesting that the DC migration-promoting role of PGE2 is independent of IL-1α/β in our model. In DC adoptive transfer experiments, EP2/EP4, but not IL-1R, was needed on the moving DCs for full-fledged migration, supporting different modes of action for PGE2 and IL-1α/β. In summary, our data highlight an important role for PGE2 in guiding DCs to dLNs in an IL-1–independent manner.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2100981
      Issue No: Vol. 208, No. 11 (2022)
       
  • miR-146a Maintains Immune Tolerance of Kupffer Cells and Facilitates
           Hepatitis B Virus Persistence in Mice [INFECTIOUS DISEASE AND HOST
           RESPONSE]

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      Authors: Liu, Y; Qin, L, Wang, J, Xie, X, Zhang, Y, Li, C, Guan, Z, Qian, L, Chen, L, Hu, J, Meng, S.
      Pages: 2558 - 2572
      Abstract: Kupffer cells (KCs), the largest tissue-resident macrophage population in the body, play a central role in maintaining a delicate balance between immune tolerance and immunity in the liver. However, the underlying molecular mechanism remains elusive. In this study, we show that KCs express high levels of miR-146a, which is under control of the PU.1 transcription factor. miR-146a deficiency promoted KCs differentiation toward a proinflammatory phenotype; conversely, miR-146a overexpression suppressed this phenotypic differentiation. We found that hepatitis B virus (HBV) persistence or HBV surface Ag treatment significantly upregulated miR-146a expression and thereby impaired polarization of KCs toward a proinflammatory phenotype. Furthermore, in an HBV carrier mouse model, KCs depletion by clodronate liposomes dramatically promoted HBV clearance and enhanced an HBV-specific hepatic CD8+ T cell and CD4+ T cell response. Consistent with this finding, miR-146a knockout mice cleared HBV faster and elicited a stronger adaptive antiviral immunity than wild-type mice. In vivo IL-12 blockade promoted HBV persistence and tempered the HBV-specific CTL response in the liver of miR-146a knockout mice. Taken together, our results identified miR-146a as a critical intrinsic regulator of an immunosuppressive phenotype in KCs under inflammatory stimuli, which may be beneficial in maintenance of liver homeostasis under physiological condition. Meanwhile, during HBV infection, miR-146a contributed to viral persistence by inhibiting KCs proinflammatory polarization, highlighting its potential as a therapeutic target in HBV infection.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2100618
      Issue No: Vol. 208, No. 11 (2022)
       
  • Clonotypic IgH Response against Systemic Viral infection in Pronephros and
           Spleen of a Teleost Fish [INFECTIOUS DISEASE AND HOST RESPONSE]

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      Authors: Castro, R; Magadan, S, Jouneau, L, Mhana, V, Pham, H.-P, Mariotti-Ferrandiz, E, Six, A, Huetz, F, Boudinot, P.
      Pages: 2573 - 2582
      Abstract: Upon infection, B lymphocytes develop clonal responses. In teleost fish, which lack lymph nodes, the kinetics and location of B cell responses remain poorly characterized. Fish pronephros is the site of B cell differentiation and the main niche for persistence of plasma cells. In this study, we undertook the analysis of the rainbow trout IgHμ repertoire in this critical tissue for humoral adaptive immunity after primary immunization and boost with a rhabdovirus, the viral hemorrhagic septicemia virus (VHSV). We used a barcoded 5' RACE-cDNA sequencing approach to characterize modifications of the IgHμ repertoire, including VH usage in expressed V(D)J rearrangements, clonal diversity, and clonotype sharing between individual fish and treatments. In the pronephros, our approach quantified the clonotype frequency across the whole IgH repertoire (i.e., with all VH), measuring the frequency of Ag-responding clonotypes. Viral infection led to extensive modifications of the pronephros B cell repertoire, implicating several VH subgroups after primary infection. In contrast, only modest changes in repertoire persisted 5 mo later, including VHSV-specific public expansions. The IgM public response implicating IgHV1-18 and JH5, previously described in spleen, was confirmed in pronephros in all infected fish, strongly correlated to the response. However, the distribution of top clonotypes showed that pronephros and spleen B cells constitute distinct compartments with different IgH repertoires. Unexpectedly, after boost, the frequency of anti-VHSV clonotypes decreased both in pronephros and spleen, raising questions about B cell circulation. A better monitoring of B cell response kinetics in lymphoid tissues will be an essential step to understand B memory and plasmocyte formation mechanisms in fish.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2200088
      Issue No: Vol. 208, No. 11 (2022)
       
  • Poor-Quality V{beta} Recombination Signal Sequences and the DNA Damage
           Response ATM Kinase Collaborate to Establish TCR{beta} Gene Repertoire and
           Allelic Exclusion [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

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      Authors: Wu, G. S; Culberson, E. J, Allyn, B. M, Bassing, C. H.
      Pages: 2583 - 2592
      Abstract: The monoallelic expression (allelic exclusion) of diverse lymphocyte Ag receptor genes enables specific immune responses. Allelic exclusion is achieved by asynchronous initiation of V(D)J recombination between alleles and protein encoded by successful rearrangement on the first allele signaling permanent inhibition of V rearrangement on the other allele. The ATM kinase that guides DNA repair and transiently suppresses V(D)J recombination also helps impose allelic exclusion through undetermined mechanisms. At the TCRβ locus, one Vβ gene segment (V31) rearranges only by inversion, whereas all other Vβ segments rearrange by deletion except for rare cases in which they rearrange through inversion following V31 rearrangement. The poor-quality recombination signal sequences (RSSs) of V31 and V2 help establish TCRβ gene repertoire and allelic exclusion by stochastically limiting initiation of Vβ rearrangements before TCRβ protein-signaled permanent silencing of Vβ recombination. We show in this study in mice that ATM functions with these RSSs and the weak V1 RSS to shape TCRβ gene repertoire by restricting their Vβ segments from initiating recombination and hindering aberrant nonfunctional Vβ recombination products, especially during inversional V31 rearrangements. We find that ATM collaborates with the V1 and V2 RSSs to help enforce allelic exclusion by facilitating competition between alleles for initiation and functional completion of rearrangements of these Vβ segments. Our data demonstrate that the fundamental genetic DNA elements that underlie inefficient Vβ recombination cooperate with ATM-mediated rapid DNA damage responses to help establish diversity and allelic exclusion of TCRβ genes.
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2100489
      Issue No: Vol. 208, No. 11 (2022)
       
  • Correction: Myeloid-Specific Deficiency of Long-Chain Acyl CoA Synthetase
           4 Reduces Inflammation by Remodeling Phospholipids and Reducing Production
           

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      Authors: Reeves, A. R; Sansbury, B. E, Pan, M, Han, X, Spite, M, Greenberg, A. S.
      Pages: 2593 - 2593
      PubDate: 2022-05-20T06:49:23-07:00
      DOI: 10.4049/jimmunol.2200133
      Issue No: Vol. 208, No. 11 (2022)
       
 
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