Immunology
Abstract
Lymph node stromal cells (LNSC) regulate immunity through constructing lymphocyte niches. LNSC produced Laminin α5 (Lama5) regulates CD4 T cells but the underlying mechanisms of its functions are poorly understood. Here we showed depleting Lama5 in LNSC resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEV). Lama5 depletion affected LN structure with increased HEV, upregulated chemokines and cell adhesion molecules, and led to greater numbers of Treg in T cell zone. Mouse and human T cell transendothelial migration and T cell entry to LN were suppressed by Lama5 through the receptors a6 integrin and α-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen specific CD4 T cell entry to the CR through HEV, suppressed T cell activation and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4:Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. The study delineated a stromal Lama5-T cell receptors axis that can be targeted for immune tolerance modulation.
Authors
Lushen Li, Marina W. Shirkey, Tianshu Zhang, Yanbao Xiong, Wenji Piao, Vikas Saxena, Christina Paluskievicz, Young S. Lee, Nicholas Toney, Benjamin M. Cerel, Qinshan Li, Thomas Simon, Kyle D. Smith, Keli L. Hippen, Bruce R. Blazar, Reza Abdi, Jonathan S. Bromberg
Abstract
Plasmacytoid dendritic cells (pDCs) are robust producers of interferon α (IFNα) and one of the first immune cells to respond to simian immunodeficiency virus infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). An increased frequency of partially activated pDCs was observed in the blood prior to detection of HIV RNA. Concurrent with peak pDC frequency, there was a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased interferon regulatory factory 7 (IRF7) and NF-kB phosphorylation. Levels of phosphorylated IRF7 and NF-kB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data, from a limited cohort, provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.
Authors
Julie L. Mitchell, Hiroshi Takata, Roshell Muir, Donn J. Colby, Eugene Kroon, Trevor A. Crowell, Carlo Sacdalan, Suteeraporn Pinyakorn, Suwanna Pattamaswin, Khunthalee Benjapornpong, Rapee Trichavaroj, Randall L. Tressler, Lawrence Fox, Victoria R. Polonis, Diane L. Bolton, Frank Maldarelli, Sharon R. Lewin, Elias K. Haddad, Praphan Phanuphak, Merlin L. Robb, Nelson L. Michael, Mark de Souza, Nittaya Phanuphak, Jintanat Ananworanich, Lydie Trautmann
Abstract
An in-depth understanding of immune escape mechanisms in cancer are likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several pre-clinical tumor models as well as clinical specimens, we report a newly identified mechanism whereby CD8+ T cell activation in response to PD-1 blockade induced a PD-L1-NLRP3 inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting anti-tumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic adaptive resistance mechanism to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Authors
Balamayooran Theivanthiran, Kathy S. Evans, Nicholas C. DeVito, Michael P. Plebanek, Michael Sturdivant, Lucas P. Wachsmuth, April K.S. Salama, Yubin Kang, David Hsu, Justin M. Balko, Douglas B. Johnson, Mark Starr, Andrew B. Nixon, Alisha Holtzhausen, Brent A. Hanks
Abstract
Fibroblasts are key-effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation maybe initiated by external factors, prolonged activation can induce an “autonomous”, self-maintaining pro-fibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role to establish this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, transforming growth factor-β (TGFβ) induced the expression of DNA-methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of signal transducers and activators of transcription 3 (STAT3) to promote fibroblast-to–myofibroblast transition, collagen release and fibrosis in vitro and in vivo. Re-establishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGFβ-dependent fibroblast activation and ameliorated experimental fibrosis in murine models. These findings identify a novel pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of new targeted therapies in fibrotic diseases.
Authors
Clara Dees, Sebastian Pötter, Yun Zhang, Christina Bergmann, Xiang Zhou, Markus Luber, Thomas Wohlfahrt, Emmanuel Karouzakis, Andreas Ramming, Kolja Gelse, Akihiko Yoshimura, Rudolf Jaenisch, Oliver Distler, Georg Schett, Jörg H.W. Distler
Abstract
Colitis caused by C. difficile infection is an increasing cause of human morbidity and mortality, especially after antibiotic use in healthcare settings. The natural immunity of newborn infants and protective host immune mediators against C. difficile infection are not fully understood, with data suggesting that inflammation can be either protective or pathogenic. Here we show an essential role for IL-17A produced by γδ T cells in host defense against C. difficile infection. Fecal extracts of children with C. difficile infection showed increased IL-17A and T cell receptor γ-chain expression, and IL-17 production by intestinal γδ T cells was efficiently induced after infection in mice. C. difficile induced tissue inflammation and mortality were each significantly increased in mice deficient in IL-17A or γδ T cells. neonatal mice, with naturally expanded ROR-γ+ γδ T cells poised for IL-17 production were resistant to C. difficile infection, whereas eliminating γδ T cells or IL-17A each efficiently overturned neonatal resistance against infection. These results reveal an expanded role for IL-17 producing γδ T cells in neonatal host defense against infection and provide a mechanistic explanation for the clinically observed resistance of infants to C. difficile colitis.
Authors
Yee-Shiuan Chen, Iuan-Bor Chen, Giang Pham, Tzu-Yu Shao, Hansraj Bangar, Sing Sing Way, David B. Haslam
Abstract
Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of thirty-five untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in systemic sclerosis patients. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction..
Authors
Takashi Maehara, Naoki Kaneko, Cory Adam Perugino, Hamid Mattoo, Jesper Kers, Hugues Allard-Chamard, Vinay S. Mahajan, Hang Liu, Samuel J.H. Murphy, Musie Ghebremichael, David A. Fox, Aimee S. Payne, Robert Lafyatis, John H. Stone, Dinesh Khanna, Shiv Pillai
Abstract
Antigen receptor–dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery, and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein–coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell–type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.
Authors
Jing Cheng, Linda R. Klei, Nathaniel E. Hubel, Ming Zhang, Rebekka Schairer, Lisa M. Maurer, Hanna B. Klei, Heejae Kang, Vincent J. Concel, Phillip C. Delekta, Eric V. Dang, Michelle A. Mintz, Mathijs Baens, Jason G. Cyster, Narayanan Parameswaran, Margot Thome, Peter C. Lucas, Linda M. McAllister-Lucas
Abstract
BACKGROUND. The live attenuated BPZE1 vaccine candidate induces protection against B. pertussis and prevents nasal colonization in animal models. Here we report on the responses in humans receiving a single intranasal administration of BPZE1. METHODS. We performed multiple assays to dissect the immune responses induced in humans (n=12) receiving BPZE1, with particular emphasis on the magnitude and characteristics of the antibody responses. Such responses were benchmarked to adolescents (n=12) receiving the complete vaccination program of the currently used acellular pertussis vaccine (aPV). Using immunoproteomics analysis, novel immunogenic B. pertussis antigens were identified. RESULTS. All BPZE1 vaccinees showed robust B. pertussis-specific antibody responses with regard to significant increase in one or more of the parameters IgG, IgA and memory B cells to B. pertussis antigens. BPZE1-specific T cells showed a Th1 phenotype and the IgG exclusively consisted of IgG1 and IgG3. In contrast, all aPV vaccinees showed a Th2-biased response. Immunoproteomics profiling revealed that BPZE1 elicited broader and different antibody specificities to B. pertussis antigens as compared to the aPV that primarily induced antibodies to the vaccine antigens. Moreover, BPZE1 was superior at inducing opsonizing antibodies that stimulated reactive oxygen species (ROS) production in neutrophils and enhanced bactericidal function, which was in line with that antibodies against adenylate cyclase toxin were only elicited by BPZE1. CONCLUSIONS. The breadth of the antibodies, the Th1-type cellular response and killing mechanisms elicited by BPZE1 may hold prospects of improving vaccine efficacy and protection against B. pertussis transmission. TRIAL REGISTRATION. ClinicalTrials.gov NCT02453048, NCT00870350 FUNDING. ILiAD Biotechnologies, Swedish Research Council (Vetenskapsrådet), Swedish Heart-lung Foundation.
Authors
Ang Lin, Danijela Apostolovic, Maja Jahnmatz, Frank Liang, Sebastian Ols, Teghesti Tecleab, Chenyan Wu, Marianne van Hage, Ken Solovay, Keith Rubin, Camille Locht, Rigmor Thorstensson, Marcel Thalen, Karin Loré
Abstract
Macrophages have been linked to tumor initiation, progression, metastasis and treatment resistance. However, the transcriptional regulation of macrophages driving the pro-tumor function remains elusive. Here, we demonstrate that the transcription factor c-Maf is a critical controller for immunosuppressive macrophage polarization and function in cancer. c-Maf controls many M2-related genes and has direct binding sites within a conservative non-coding sequence of csf-1r gene and promotes M2-like macrophage-mediated T cell suppression and tumor progression. c-Maf also serves as a metabolic checkpoint regulating TCA cycle and UDP-GlcNAc biosynthesis thus promoting M2-like macrophage polarization and activation. Additionally, c-Maf is highly expressed in tumor-associated macrophages (TAM) and regulates TAM immunosuppressive function. Deletion of c-Maf specifically in myeloid cells results in reduced tumor burden with enhanced antitumor T cell immunity. Inhibition of c-Maf partly overcomes resistance to anti-PD-1 therapy in a subcutaneous LLC tumor model. Similarly, c-Maf is expressed in human M2 and tumor-infiltrating macrophages/monocytes as well as circulating monocytes of human non-small cell lung carcinoma (NSCLC) patients and critically regulates its immunosuppressive activity. Natural compound β-glucan downregulates c-Maf expression on macrophages leading to enhanced antitumor immunity in mice. These findings establish a paradigm for immunosuppressive macrophage polarization and transcriptional regulation by c-Maf and suggest that c-Maf is a potential target for effective tumor immunotherapy.
Authors
Min Liu, Zan Tong, Chuanlin Ding, Fengling Luo, Shouzhen Wu, Caijun Wu, Sabrin Albeituni, Liqing He, Xiaoling Hu, David Tieri, Eric C. Rouchka, Michito Hamada, Satoru Takahashi, Andrew A. Gibb, Goetz Kloecker, Huang-Ge Zhang, Michael Bousamra, Bradford G. Hill, Xiang Zhang, Jun Yan
Abstract
Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the pro-inflammatory cytokine interleukin-1β (IL1β) in obesity. While this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. These studies investigated whether visceral adipose NLRP3 impairs cognition by activating microglial interleukin-1 receptor 1 (IL1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3KO mice, we transplanted VAT from obese WT or NLRP3KO donors into lean recipients. Transplantation of VAT from a WT donor (TRANSWT) increased hippocampal IL1β and impaired cognition, but VAT transplants from comparably obese NLRP3KO donors (TRANSKO) had no effect. Visceral adipose NLRP3 was required for deficits in long-term potentiation (LTP) in transplant recipients, and LTP impairment in TRANSWT mice was IL1-dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL1β gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL1R1 in CX3CR1-expressing cells eliminated cognitive impairment in mice with dietary obesity and in transplant recipients and restored immunoquiescence in hippocampal microglia. These results indicate that visceral adipose NLRP3 impairs memory via IL1-mediated microglial activation, and suggest that NLRP3-IL1β signaling may underlie correlations between visceral adiposity and cognitive impairment in humans.
Authors
De-Huang Guo, Masaki Yamamoto, Caterina M. Hernandez, Hesam Khodadadi, Babak Baban, Alexis M. Stranahan
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)