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| Open AccessConsistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs
Xenotransplantation is an imminent clinical reality but concerns remain around the logistics of procurement and the experimental immunosuppression regimens required to achieve long-term xenograft survival. Here the authors show more than 6 month survival of genetically modified porcine kidneys in baboons after regulatory compliant organ procurements, clinically relevant organ preservation times and FDA-approved immunosuppressive reagents.
- Daniel Eisenson
- , Yu Hisadome
- & Kazuhiko Yamada
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Article
| Open AccessDonor regulatory T cells rapidly adapt to recipient tissues to control murine acute graft-versus-host disease
Graft-versus-Host disease is a major complication after allogeneic bone marrow transplantation and is ameliorated by adoptively transferred donor regulatory T cells. Here, the authors apply transcriptomic and TCR profiling to assess regulatory T cell organ-specific adaptation in murine bone marrow transplantation models.
- David J. Dittmar
- , Franziska Pielmeier
- & Michael Rehli
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Article
| Open AccessFOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity
Modulation of regulatory T cells (Treg) in the tumour environment is a potential avenue to bolster anti-tumor immunity. Here Liu et al show that perturbation of the negative feedback loop involving STAT1- IFITM3 influences anti-tumor immunity, and that IFITM3 or STAT1 deficiency resulting in the fragility of tumor-infiltrating Treg cells.
- Xinnan Liu
- , Weiqi Zhang
- & Bin Li
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Article
| Open AccessCAR+ and CAR− T cells share a differentiation trajectory into an NK-like subset after CD19 CAR T cell infusion in patients with B cell malignancies
Phenotype of cells in the infusion product as well at specific post-infusion time points has been associated with clinical response to CD19 CAR T cells. Here the authors present a single-cell multi-omics analysis of pre- and post-infusion CAR+ and CAR- T cells from patients with relapsed or refractory B-ALL or LBCL who received CD19 CAR T therapy.
- Raymond Hall Yip Louie
- , Curtis Cai
- & Fabio Luciani
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Article
| Open AccessTHBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
Thrombospondin-1 (THBS1) is a matricellular protein highly expressed in inflammatory processes, including cancer. Here the authors show that bone-marrow derived monocyte-like cells are the primary source of THBS1 in colorectal cancer, associated with mesenchymal characteristics, immunosuppression and a poor prognosis.
- Mayuki Omatsu
- , Yuki Nakanishi
- & Hiroshi Seno
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Article
| Open AccessTumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer
Patients with MMR-proficient, microsatellite stable (MSS) colorectal cancer (CRC) are highly resistant to immune-checkpoint inhibitors. Here the authors report that tumor intrinsic expression of the autophagy gene ATG16L1 is associated with resistance to anti-tumor immunity in preclinical CRC models and that elevated ATG16L1 expression predicts poor immunotherapy response in Kras-mutant CRC patients.
- Lucia Taraborrelli
- , Yasin Şenbabaoğlu
- & Aditya Murthy
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Article
| Open AccessIntracellular Fusobacterium nucleatum infection attenuates antitumor immunity in esophageal squamous cell carcinoma
Fusobacterium nucleatum (Fn) is an oncogenic bacterium reported to promote esophageal squamous cell carcinoma (ESCC). Here the authors show that the virulence factor of Fn, Fn-Dps upregulates PD-L1 and that Fn promotes cell death in T-cells, hence, limiting the efficacy of immunotherapy in ESCC.
- Yiqiu Li
- , Shan Xing
- & Ge Zhang
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Article
| Open AccessMulti-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1
Mesenchymal stem cells (MSC) are used for immunosuppressive therapy and a uniform source or heterogeneity characterisation is needed. Here the authors use multi-omics to compare human MSC from different sources and ages of donors and show differences in gene expression and immunosuppressive function.
- Yuchen Gao
- , Ying Chi
- & Xiaomin Zhang
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Article
| Open AccessGas therapy potentiates aggregation-induced emission luminogen-based photoimmunotherapy of poorly immunogenic tumors through cGAS-STING pathway activation
Gas-based therapy is an emerging therapeutic option for cancer treatment. Here the authors design a virus-mimicking hollow mesoporous tetrasulfide-doped organosilica for co-encapsulation of an aggregation-induced emission (AIE)-active luminogen and manganese carbonyl to fabricate a STING activating gas nano-adjuvant for photo-immunotherapy, promoting anti-tumor immune response in preclinical models.
- Kaiyuan Wang
- , Yang Li
- & Xiaoyuan Chen
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Article
| Open AccessLow-dose IL-2 enhances the generation of IL-10-producing immunoregulatory B cells
The dysfunction of IL-10 secreting regulatory B cells has been linked to the pathogenesis of autoimmune disease. Here the authors show that low dose IL-2 therapy can enhance IL-10 production in regulatory B cell populations via the modulation of BACH2.
- Akimichi Inaba
- , Zewen Kelvin Tuong
- & Menna R. Clatworthy
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Article
| Open AccessReprogramming systemic and local immune function to empower immunotherapy against glioblastoma
Glioblastoma (GBM) is characterized by local and systemic immunosuppression, showing limited responses to immunotherapies. Here the authors describe the design of a nanoplatform composed of the lymphopenia alleviating agent cannabidiol and the lymphocyte recruiting cytokine LIGHT, promoting anti-tumor immune responses in GBM preclinical models.
- Songlei Zhou
- , Yukun Huang
- & Jun Chen
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Article
| Open AccessCostimulation blockade in combination with IL-2 permits regulatory T cell sparing immunomodulation that inhibits autoimmunity
The blockade of CD28 signalling is known to reduce pathological T cell responses in the context of both autoimmunity and transplantation, but has been associated with impairment of the regulatory T cell compartment. Here the authors show combining costimulation blockade with the administration of interleukin 2 selectively impairs the T effector response whilst maintaining the regulatory T cell pool and suggest functional effect in a murine model of autoimmune diabetes.
- Chun Jing Wang
- , Lina Petersone
- & Lucy S. K. Walker
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Article
| Open AccessMetabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion
Chemo-resistance and immune evasion are major challenges in osteosarcoma treatment. Here the authors show that doxorubicin promotes IL-18 secretion by tumor associated macrophages inducing LAT2-dependent CD47 upregulation in osteosarcoma cells, suggesting LAT2 inhibition as a therapeutic option in combination with doxorubicin.
- Zenan Wang
- , Binghao Li
- & Zhaoming Ye
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Article
| Open AccessCo-expression of a PD-L1-specific chimeric switch receptor augments the efficacy and persistence of CAR T cells via the CD70-CD27 axis
Co-expression of PD-L1-specific chimeric switch receptors (CSRs) improves the antitumor effects of chimeric antigen receptor (CAR) T cells. Here, CSRs are shown to promote the differentiation of mesothelin-targeting CAR T cells into central memory-like cells and improve their efficacy.
- Le Qin
- , Yuanbin Cui
- & Peng Li
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Article
| Open AccessNoninvasive imaging of the tumor immune microenvironment correlates with response to immunotherapy in gastric cancer
Tumour microenvironment has been linked with immunotherapy response in gastric cancer. Here, the authors use CT-based radiomics to predict neutrophils-to-lymphocyte ratio and response to immunotherapy.
- Weicai Huang
- , Yuming Jiang
- & Guoxin Li
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Article
| Open AccessEx vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis
Human regulatory B (Breg) cells have been difficult to study due to their scarcity and heterogeneity. Here the authors expand human B cells to exert immunosuppressive function in vitro and in vivo, and to implicate the TIM-1/STAT3 axis for the regulation of their homoeostasis and function.
- S. Shankar
- , J. Stolp
- & K. J. Wood
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Article
| Open AccessMesenchymal stem cells transfer mitochondria to allogeneic Tregs in an HLA-dependent manner improving their immunosuppressive activity
Regulatory T (Treg) cells and mesenchymal stem cells (MSCs) are both cell populations capable of immune tolerance induction. Here the authors show that the transfer of mitochondria from mesenchymal stem cells to allogeneic Treg cells in an HLA-dependent manner results in enhanced immunosuppressive functions of Treg cells.
- Karolina Piekarska
- , Zuzanna Urban-Wójciuk
- & Natalia Maria Marek-Trzonkowska
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Article
| Open AccessGPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models
Immunologically cold tumours don’t respond to immune checkpoint blockade inhibition due to poor recruitment of anti-tumour T cells. Authors show here that melanoma-associated lymphatic endothelial cells express G Protein-Coupled Receptor 182 that scavenges CXCL9 and other chemokines necessary for T cell recruitment.
- Robert J. Torphy
- , Yi Sun
- & Yuwen Zhu
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Article
| Open AccessDepletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab
Elimination of regulatory T cells via the anti-CCR4 monoclonal antibody, mogamulizumab, is expected to augment anti-tumour immune response. Authors show here that although regulatory T cell targeting is successful, clinical improvement remains minimal in patients with solid tumours due to concomitant and unintended depletion of central memory CD8+ T cells.
- Yuka Maeda
- , Hisashi Wada
- & Hiroyoshi Nishikawa
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Article
| Open AccessMesenchymal stromal cell apoptosis is required for their therapeutic function
Mesenchymal stromal cells (MSCs) demonstrate therapeutic benefits in multiple diseases, but the mechanisms remain unclear as infused MSCs do not persist in the body. Here, the authors show that MSC apoptosis is an important mechanistic element, as MSCs rendered genetically incapable of apoptosis lose their ability to ameliorate disease.
- Swee Heng Milon Pang
- , Joshua D’Rozario
- & Tracy S. P. Heng
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Article
| Open AccessRegulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation
TGFβ is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGFβ is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGFβ dependent tumor growth.
- Alexandra Lainé
- , Ossama Labiad
- & Julien C. Marie
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Article
| Open AccessC3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates
Donor-specific antibodies in sensitized recipients may cause kidney transplant rejection. Here the authors show that complement component C3 inhibition prolongs graft survival by inhibiting T and B cell proliferation/activation and hence tissue injury, despite antibody levels remaining unaffected.
- Robin Schmitz
- , Zachary W. Fitch
- & Stuart J. Knechtle
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Article
| Open AccessThe survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5
Regulatory B (Breg) cells suppress excessive inflammation primary via the production of interleukin 10 (IL-10). Here the authors show that the function and homeostasis of mouse and human IL-10+ Breg cells are negatively regulated by the cell surface receptor, SLAMF5, to impact experimental autoimmunity, thereby hinting SLAMF5 as a potential target for immunotherapy.
- Lihi Radomir
- , Matthias P. Kramer
- & Idit Shachar
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Article
| Open AccessCD4 derived double negative T cells prevent the development and progression of nonalcoholic steatohepatitis
Hepatic inflammation contributes to the development of nonalcoholic steatohepatitis (NASH). Here, the authors show that a transfer of ex vivo generated CD4 derived double negative T cells can prevent the development and progression of NASH by suppression of inflammatory Th17 cells and M1 macrophages in mouse models.
- Guangyong Sun
- , Xinyan Zhao
- & Dong Zhang
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Article
| Open AccessSelective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer
Inhibiting TGF-β1 to increase immune responses against tumors bears the risk of tumor-promoting toxicity. Here the authors show that selectively blocking TGF-β1 produced by immunosuppressive cells is feasible with anti-GARP:TGF-β1 antibodies and improves the efficacy of PD-1 blockade immunotherapy.
- Grégoire de Streel
- , Charlotte Bertrand
- & Sophie Lucas
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Article
| Open AccessBlockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine
The tryptophan metabolite kynurenine is an endogenous ligand of the aryl hydrocarbon receptor (AHR). Here, the authors show that AHR targeting in IDO/TDO-expressing tumours counteracts a regulatory T cell/macrophage suppressive axis and synergizes with immune checkpoint blockade to hinder tumour growth.
- Luis Felipe Campesato
- , Sadna Budhu
- & Jedd D. Wolchok
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Article
| Open AccessHigh-salt diet inhibits tumour growth in mice via regulating myeloid-derived suppressor cell differentiation
High-salt intake can promote pro-inflammatory responses associated with pathological conditions. However, here, the authors show that high-salt diet may have an antitumor protective role by modulating the accumulation and phenotype of myeloid derived suppressor cells and enhancing immunosurveillance.
- Wei He
- , Jinzhi Xu
- & Lei Dong
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Article
| Open AccessCD73 on cancer-associated fibroblasts enhanced by the A2B-mediated feedforward circuit enforces an immune checkpoint
Our understanding on how CAFs can be activated to support tumour progression is still limited. Here, the authors demonstrate that adenosine produced in the tumour microenvironment can enhance the expression of CD73 in CAFs ultimately driving CD8 T-Cell suppression and tumour growth.
- Miao Yu
- , Gang Guo
- & Yan Cui
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Article
| Open AccessDouble negative T cells mediate Lag3-dependent antigen-specific protection in allergic asthma
Allergic asthma symptoms may be controlled, but currently no effective therapy exist to address the underlying pathology. Here the authors show, using mouse model of adoptive cell transfer, that CD4-CD8- T cells can suppress the function of dendritic cells and T follicular helper cells via Lag3 to provide allergen-specific protection from asthma.
- Dan Tian
- , Lu Yang
- & Dong Zhang
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Article
| Open AccessPD-1 blockade potentiates HIV latency reversal ex vivo in CD4+ T cells from ART-suppressed individuals
The immune checkpoint molecule PD-1 is expressed on a fraction of CD4+ T cells latently infected with HIV, but whether PD-1 plays a functional role in reservoir persistence remains unknown. Here, Fromentin et al. show that PD-1 blockade potentiates latency reversal ex vivo in CD4+ T cells from ART suppressed individuals.
- Rémi Fromentin
- , Sandrina DaFonseca
- & Nicolas Chomont
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Article
| Open AccessInduction of immunosuppressive functions and NF-κB by FLIP in monocytes
Signaling and transcriptional regulation of MDSC activity remains largely undefined. Here the authors show that monocytic MDSC immunosuppression is triggered by c-FLIP and requires NFκB, implicate this axis in cancer prognosis and response to therapy, and employ ectopic FLIP to treat immunopathology.
- Alessandra Fiore
- , Stefano Ugel
- & Vincenzo Bronte
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Article
| Open AccessTIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity
Regulatory macrophages (Mreg) can directly suppress T effector cell responses. Here the authors show that human Mreg also elicit TIGIT+ regulatory T cells by integrating multiple differentiation signals, and that donor Mreg-induced recipient Tregs may promote kidney transplant acceptance in patients.
- Paloma Riquelme
- , Jan Haarer
- & James A. Hutchinson
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Article
| Open AccessRegulatory T cells control toxicity in a humanized model of IL-2 therapy
High dose IL-2 is a viable treatment option for cancer immune therapy, but the underlying mechanism for the accompanying undesirable morbidity is unclear. Here the authors show, using human immune system mouse models, that regulatory T cells and their functions on effector T cells are essential modulators of the related pathogenesis.
- Yan Li
- , Helene Strick-Marchand
- & James P. Di Santo
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Article
| Open AccessHost STING-dependent MDSC mobilization drives extrinsic radiation resistance
Tumors often develop resistance to radiotherapy. Here the authors show that irradiation leads to a CCR2-dependent infiltration by myeloid derived suppressor cells that promote radio-resistance through inhibition of adaptive immune responses and that the use of CCR2 antibodies in mice reduces such resistance.
- Hua Liang
- , Liufu Deng
- & Ralph R. Weichselbaum
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Article
| Open AccessGlucocorticoid-induced phosphorylation by CDK9 modulates the coactivator functions of transcriptional cofactor GRIP1 in macrophages
Glucocorticoid reduces inflammation by both inducing anti-inflammatory genes and suppressing pro-inflammatory genes, but how these two functions are dictated is unclear. Here the authors show that phosphorylated glucocorticoid receptor-interacting protein 1 (GRIP1) serves as a coactivator for this response in macrophage.
- David A. Rollins
- , Joubert B. Kharlyngdoh
- & Inez Rogatsky
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Article
| Open AccessIntertwining DNA-RNA nanocapsules loaded with tumor neoantigens as synergistic nanovaccines for cancer immunotherapy
Nucleic acid nanomedicines are promising for cancer drug delivery. Here, the authors show using a mouse model the tumor immunotherapeutic efficacy of nanovaccines based on intertwining DNA-RNA nanocapsules loaded with DNA CpG, Stat3-silencing short hairpin RNA and tumor-specific peptide neoantigens.
- Guizhi Zhu
- , Lei Mei
- & Xiaoyuan Chen
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Article
| Open AccessSuppressive IL-17A+Foxp3+ and ex-Th17 IL-17AnegFoxp3+ Treg cells are a source of tumour-associated Treg cells
Th17 cells can transdifferentiate into regulatory T (Treg) cells. Here the authors characterize tumour-driven Th17-to-Tregcell transdifferentiation and identify potential cancer therapy targets.
- Stephanie Downs-Canner
- , Sara Berkey
- & Nataša Obermajer
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Article
| Open AccessT cell costimulation blockade blunts pressure overload-induced heart failure
Abatacept is an FDA-approved drug used for treatment of rheumatoid arthritis. Here the authors show that abatacept reduces cardiomyocyte death in a mouse model of heart failure by inhibiting activation and heart infiltration of T cells and macrophages, an effect mediated by IL-10, suggesting a potential therapy for heart failure.
- Marinos Kallikourdis
- , Elisa Martini
- & Gianluigi Condorelli
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Review Article
| Open AccessRecommendations for myeloid-derived suppressor cell nomenclature and characterization standards
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population expanded in cancer and other chronic inflammatory conditions. Here the authors identify the challenges and propose a set of minimal reporting guidelines for mouse and human MDSC.
- Vincenzo Bronte
- , Sven Brandau
- & Dmitry I. Gabrilovich
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Article
| Open AccessStromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
The risk of developing cancer increases with age. Here, the authors address the contribution of age-dependent accumulation of senescent cells within the tumour stroma compartment and show that senescent cells increase the infiltration of myeloid-derived suppressor cells that inhibit cytotoxic T-cells, thus facilitating tumour outgrowth.
- Megan K. Ruhland
- , Andrew J. Loza
- & Sheila A. Stewart
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Article |
Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells
The need to develop vaccines against pathogens such as HIV requires the development of strategies to overcome inhibitory immunoregulatory mechanisms. Here, the authors report that murine natural killer cells inhibit CD4- and follicular helper T cells, leading to a weaker germinal center response and diminished virus-specific immune memory.
- Carolyn Rydyznski
- , Keith A. Daniels
- & Stephen N. Waggoner
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Article |
An IL-27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction
Tim-3 is an inhibitory molecule that suppresses T-cell responses. Here the authors show that the cytokine IL-27, acting through the transcription factor NFIL3, induces Tim-3 in vivo, and that IL-27-conditioned Th1 cells have poor effector function.
- Chen Zhu
- , Kaori Sakuishi
- & Vijay K. Kuchroo
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Article
| Open AccessGlucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M
Glucocorticoids strongly suppress inflammation. Here the authors show that this suppression is mediated by induction of the negative inflammatory regulator IRAK-M, and demonstrate its important role in host defense against the pneumonia-causative bacterium, non-typeable Haemophilus influenzae.
- Masanori Miyata
- , Ji-Yun Lee
- & Jian-Dong Li