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1.
Immunity ; 52(3): 528-541.e7, 2020 03 17.
Article in English | MEDLINE | ID: mdl-32160525

ABSTRACT

Helminths, allergens, and certain protists induce type 2 immune responses, but the underlying mechanisms of immune activation remain poorly understood. In the small intestine, chemosensing by epithelial tuft cells results in the activation of group 2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance. ILC2 activation requires tuft-cell-derived interleukin-25 (IL-25), but whether additional signals regulate the circuit is unclear. Here, we show that tuft cells secrete cysteinyl leukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing of helminth infection. CysLTs cooperate with IL-25 to activate ILC2s, and tuft-cell-specific ablation of leukotriene synthesis attenuates type 2 immunity and delays helminth clearance. Conversely, cysLTs are dispensable for the tuft cell response induced by intestinal protists. Our findings identify an additional tuft cell effector function and suggest context-specific regulation of tuft-ILC2 circuits within the small intestine.


Subject(s)
Cysteine/immunology , Intestinal Mucosa/immunology , Intestine, Small/immunology , Leukotrienes/immunology , Nippostrongylus/immunology , Strongylida Infections/immunology , Animals , Arachidonate 5-Lipoxygenase/genetics , Arachidonate 5-Lipoxygenase/immunology , Arachidonate 5-Lipoxygenase/metabolism , Cysteine/metabolism , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/parasitology , Immunity, Innate/immunology , Interleukin-17/genetics , Interleukin-17/immunology , Interleukin-17/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/parasitology , Intestine, Small/cytology , Intestine, Small/metabolism , Leukotrienes/metabolism , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/parasitology , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Nippostrongylus/physiology , Strongylida Infections/parasitology
2.
J Immunol ; 208(5): 1007-1020, 2022 03 01.
Article in English | MEDLINE | ID: mdl-35181641

ABSTRACT

E-protein transcription factors limit group 2 innate lymphoid cell (ILC2) development while promoting T cell differentiation from common lymphoid progenitors. Inhibitors of DNA binding (ID) proteins block E-protein DNA binding in common lymphoid progenitors to allow ILC2 development. However, whether E-proteins influence ILC2 function upon maturity and activation remains unclear. Mice that overexpress ID1 under control of the thymus-restricted proximal Lck promoter (ID1tg/WT) have a large pool of primarily thymus-derived ILC2s in the periphery that develop in the absence of E-protein activity. We used these mice to investigate how the absence of E-protein activity affects ILC2 function and the genomic landscape in response to house dust mite (HDM) allergens. ID1tg/WT mice had increased KLRG1- ILC2s in the lung compared with wild-type (WT; ID1WT/WT) mice in response to HDM, but ID1tg/WT ILC2s had an impaired capacity to produce type 2 cytokines. Analysis of WT ILC2 accessible chromatin suggested that AP-1 and C/EBP transcription factors but not E-proteins were associated with ILC2 inflammatory gene programs. Instead, E-protein binding sites were enriched at functional genes in ILC2s during development that were later dynamically regulated in allergic lung inflammation, including genes that control ILC2 response to cytokines and interactions with T cells. Finally, ILC2s from ID1tg/WT compared with WT mice had fewer regions of open chromatin near functional genes that were enriched for AP-1 factor binding sites following HDM treatment. These data show that E-proteins shape the chromatin landscape during ILC2 development to dictate the functional capacity of mature ILC2s during allergic inflammation in the lung.


Subject(s)
Antigens, Dermatophagoides/immunology , Asthma/immunology , Inhibitor of Differentiation Protein 1/metabolism , T-Lymphocytes/immunology , Transcription Factors/metabolism , Adaptor Proteins, Signal Transducing/genetics , Allergens/immunology , Animals , Asthma/pathology , Cell Differentiation/immunology , Chromatin/metabolism , Cytokines/immunology , DNA-Binding Proteins/antagonists & inhibitors , Female , Lectins, C-Type/genetics , Lung/immunology , Lung/pathology , Male , Mice , Mice, Inbred C57BL , Pyroglyphidae/immunology , Receptors, Immunologic/genetics , Stem Cells/cytology , T-Lymphocytes/cytology , Transcription Factor AP-1/metabolism
3.
J Immunol ; 202(5): 1321-1329, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30782851

ABSTRACT

Tuft cells were first discovered in epithelial barriers decades ago, but their function remained unclear until recently. In the last 2 years, a series of studies has provided important advances that link tuft cells to infectious diseases and the host immune responses. Broadly, a model has emerged in which tuft cells use chemosensing to monitor their surroundings and translate environmental signals into effector functions that regulate immune responses in the underlying tissue. In this article, we review the current understanding of tuft cell immune function in the intestines, airways, and thymus. In particular, we discuss the role of tuft cells in type 2 immunity, norovirus infection, and thymocyte development. Despite recent advances, many fundamental questions about the function of tuft cells in immunity remain to be answered.


Subject(s)
Immunity, Mucosal/immunology , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Animals , Humans , Surface Properties
4.
J Immunol ; 198(4): 1492-1502, 2017 02 15.
Article in English | MEDLINE | ID: mdl-28077598

ABSTRACT

Regulatory T (Treg) cells establish tolerance, prevent inflammation at mucosal surfaces, and regulate immunopathology during infectious responses. Recent studies have shown that Delta-like ligand 4 (Dll4) was upregulated on APC after respiratory syncytial virus (RSV) infection, and its inhibition leads to exaggerated immunopathology. In the present study, we outline the role of Dll4 in Treg cell differentiation, stability, and function in RSV infection. We found that Dll4 was expressed on CD11b+ pulmonary dendritic cells in the lung and draining lymph nodes in wild-type BALB/c mice after RSV infection. Dll4 neutralization exacerbated RSV-induced disease pathology, mucus production, group 2 innate lymphoid cell infiltration, IL-5 and IL-13 production, as well as IL-17A+ CD4 T cells. Dll4 inhibition decreased the abundance of CD62LhiCD44loFoxp3+ central Treg cells in draining lymph nodes. The RSV-induced disease was accompanied by an increase in Th17-like effector phenotype in Foxp3+ Treg cells and a decrease in granzyme B expression after Dll4 blockade. Finally, Dll4-exposed induced Treg cells maintained the CD62LhiCD44lo central Treg cell phenotype, had increased Foxp3 expression, became more suppressive, and were resistant to Th17 skewing in vitro. These results suggest that Dll4 activation during differentiation sustained Treg cell phenotype and function to control RSV infection.


Subject(s)
Cell Differentiation , Intracellular Signaling Peptides and Proteins/metabolism , Lung/immunology , Lung/virology , Membrane Proteins/metabolism , Respiratory Syncytial Virus Infections/immunology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/physiology , Adaptor Proteins, Signal Transducing , Animals , Calcium-Binding Proteins , Dendritic Cells/immunology , Dendritic Cells/virology , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Granzymes/genetics , Interleukin-13/immunology , Interleukin-5/immunology , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/immunology , Intracellular Signaling Peptides and Proteins/pharmacology , L-Selectin/genetics , L-Selectin/immunology , Lung/cytology , Lung/pathology , Lymphocyte Activation/drug effects , Membrane Proteins/genetics , Membrane Proteins/immunology , Membrane Proteins/pharmacology , Mice , Mice, Inbred BALB C , Respiratory Syncytial Virus Infections/physiopathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Viruses/immunology , Respiratory Syncytial Viruses/isolation & purification , Th17 Cells/drug effects , Th17 Cells/immunology
5.
Am J Pathol ; 184(6): 1807-18, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24726498

ABSTRACT

IL-27 is a heterodimeric cytokine composed of the subunits p28 and Epstein-Barr virus induced gene (EBI)-3 and is known for its effects on T-cell function and differentiation. IL-27 signals through the widely expressed IL-27 receptor (IL-27R), composed of the ligand-specific IL-27Rα chain and gp130. Engagement of the IL-27R activates STAT1 signaling, induces the expression of the type 1 helper T-cell (Th1) cytokine, interferon γ, and suppresses the differentiation of Th2 and Th17 cells. This study investigates the role of IL-27 signaling in respiratory syncytial virus (RSV) infection using IL-27Rα-deficient mice (IL-27rKO). Analysis of lungs from RSV-infected IL-27rKO mice showed exacerbation of mucus secretion compared with wild type, as well as enhanced expression of Muc5ac and Gob5 mRNA, markers of goblet cell metaplasia/hyperplasia. When compared with wild-type mice, RSV-challenged IL-27rKO mice had enhanced expression of Th17-associated cytokine IL-17a and an imbalance between Th1 and Th2 cytokine levels. Neutralization of IL-17 in RSV-infected IL-27rKO mice resulted in a significant decrease in the pulmonary mucus response and inhibition of the Th2-associated cytokines. Interestingly, IL-17 blockage led to an increase in the expression of IL-27 subunits p28 and EBI-3 in the lungs and lymph nodes of RSV-infected mice. Thus, IL-27 functions as a regulatory cytokine during RSV pathogenesis by suppressing the development of Th17 cells, but it also appears to be regulated by IL-17 induced by the virus.


Subject(s)
Interleukin-17/immunology , Receptors, Cytokine/immunology , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/immunology , Th17 Cells/immunology , Th2 Cells/immunology , Animals , Chloride Channels/genetics , Chloride Channels/immunology , Interleukin-17/genetics , Interleukins/genetics , Interleukins/immunology , Mice , Mice, Knockout , Minor Histocompatibility Antigens , Mucin 5AC/genetics , Mucin 5AC/immunology , Mucoproteins/genetics , Mucoproteins/immunology , Mucus/immunology , Receptors, Cytokine/genetics , Receptors, Interleukin , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/pathology , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/immunology , Th17 Cells/pathology , Th2 Cells/pathology
6.
J Immunother Cancer ; 11(3)2023 03.
Article in English | MEDLINE | ID: mdl-36918221

ABSTRACT

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformational outcomes in the treatment of B-cell malignancies, but their widespread use is hindered by technical and logistical challenges associated with ex vivo cell manufacturing. To overcome these challenges, we developed VivoVec, a lentiviral vector-based platform for in vivo engineering of T cells. UB-VV100, a VivoVec clinical candidate for the treatment of B-cell malignancies, displays an anti-CD3 single-chain variable fragment (scFv) on the surface and delivers a genetic payload that encodes a second-generation CD19-targeted CAR along with a rapamycin-activated cytokine receptor (RACR) system designed to overcome the need for lymphodepleting chemotherapy in supporting successful CAR T-cell expansion and persistence. In the presence of exogenous rapamycin, non-transduced immune cells are suppressed, while the RACR system in transduced cells converts rapamycin binding to an interleukin (IL)-2/IL-15 signal to promote proliferation. METHODS: UB-VV100 was administered to peripheral blood mononuclear cells (PBMCs) from healthy donors and from patients with B-cell malignancy without additional stimulation. Cultures were assessed for CAR T-cell transduction and function. Biodistribution was evaluated in CD34-humanized mice and in canines. In vivo efficacy was evaluated against normal B cells in CD34-humanized mice and against systemic tumor xenografts in PBMC-humanized mice. RESULTS: In vitro, administration of UB-VV100 resulted in dose-dependent and anti-CD3 scFv-dependent T-cell activation and CAR T-cell transduction. The resulting CAR T cells exhibited selective expansion in rapamycin and antigen-dependent activity against malignant B-cell targets. In humanized mouse and canine studies, UB-VV100 demonstrated a favorable biodistribution profile, with transduction events limited to the immune compartment after intranodal or intraperitoneal administration. Administration of UB-VV100 to humanized mice engrafted with B-cell tumors resulted in CAR T-cell transduction, expansion, and elimination of systemic malignancy. CONCLUSIONS: These findings demonstrate that UB-VV100 generates functional CAR T cells in vivo, which could expand patient access to CAR T technology in both hematological and solid tumors without the need for ex vivo cell manufacturing.


Subject(s)
Receptors, Chimeric Antigen , T-Lymphocytes , Humans , Animals , Dogs , Mice , Receptors, Chimeric Antigen/genetics , Receptors, Antigen, T-Cell , Leukocytes, Mononuclear , Tissue Distribution , Cell Engineering/methods
7.
Mucosal Immunol ; 11(5): 1524-1536, 2018 09.
Article in English | MEDLINE | ID: mdl-30038214

ABSTRACT

Notch ligand Delta-like ligand 4 (DLL4) has been shown to regulate CD4 T-cell differentiation, including regulatory T cells (Treg). Epigenetic alterations, which include histone modifications, are critical in cell differentiation decisions. Recent genome-wide studies demonstrated that Treg have increased trimethylation on histone H3 at lysine 4 (H3K4me3) around the Treg master transcription factor, Foxp3 loci. Here we report that DLL4 dynamically increased H3K4 methylation around the Foxp3 locus that was dependent upon upregulated SET and MYDN domain containing protein 3 (SMYD3). DLL4 promoted Smyd3 through the canonical Notch pathway in iTreg differentiation. DLL4 inhibition during pulmonary respiratory syncytial virus (RSV) infection decreased Smyd3 expression and Foxp3 expression in Treg leading to increased Il17a. On the other hand, DLL4 supported Il10 expression in vitro and in vivo, which was also partially dependent upon SMYD3. Using genome-wide unbiased mRNA sequencing, novel sets of DLL4- and Smyd3-dependent differentially expressed genes were discovered, including lymphocyte-activation gene 3 (Lag3), a checkpoint inhibitor that has been identified for modulating Th cell activation. Together, our data demonstrate a novel mechanism of DLL4/Notch-induced Smyd3 epigenetic pathways that maintain regulatory CD4 T cells in viral infections.


Subject(s)
Histone-Lysine N-Methyltransferase/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Viruses/physiology , T-Lymphocytes, Regulatory/immunology , Adaptor Proteins, Signal Transducing , Animals , Calcium-Binding Proteins , Cell Differentiation , Cells, Cultured , DNA Methylation , Epigenesis, Genetic , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histones/metabolism , Immune Tolerance , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction
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