Publications by authors named "Andrew D Luster"

227 Publications

Chemokines and the immune response to cancer.

Immunity 2021 May 10;54(5):859-874. Epub 2021 Apr 10.

Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Chemokines are chemotactic cytokines that regulate the migration of immune cells. Chemokines function as cues for the coordinated recruitment of immune cells into and out of tissue and also guide the spatial organization and cellular interactions of immune cells within tissues. Chemokines are critical in directing immune cell migration necessary to mount and then deliver an effective anti-tumor immune response; however, chemokines also participate in the generation and recruitment of immune cells that contribute to a pro-tumorigenic microenvironment. Here, we review the role of the chemokine system in anti-tumor and pro-tumor immune responses and discuss how malignant cells and the tumor microenvironment regulate the overall chemokine landscape to shape the type and outcome of immune responses to cancer and cancer treatment.
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http://dx.doi.org/10.1016/j.immuni.2021.01.012DOI Listing
May 2021

Targeting the Chemokine System in Rheumatoid Arthritis and Vasculitis.

JMA J 2020 Jul 13;3(3):182-192. Epub 2020 Jul 13.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, USA.

Arrest of circulating leukocytes and subsequent diapedesis is a fundamental component of inflammation. In general, the leukocyte migration cascade is tightly regulated by chemoattractants, such as chemokines. Chemokines, small secreted chemotactic cytokines, as well as their G-protein-coupled seven transmembrane spanning receptors, control the migratory patterns, positioning and cellular interactions of immune cells. Increased levels of chemokines and their receptors are found in the blood and within inflamed tissue in patients with rheumatoid arthritis (RA) and vasculitis. Chemokine ligand-receptor interactions regulate the recruitment of leukocytes into tissue, thus contributing in important ways to the pathogenesis of RA and vasculitis. Despite the fact that blockade of chemokines and chemokine receptors in animal models have yielded promising results, human clinical trials in RA using inhibitors of chemokines and their receptors have generally failed to show clinical benefits. However, recent early phase clinical trials suggest that strategies blocking specific chemokines may have clinical benefits in RA, demonstrating that the chemokine system remains a promising therapeutic target for rheumatic diseases, such as RA and vasuculitis and requires further study.
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http://dx.doi.org/10.31662/jmaj.2020-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590389PMC
July 2020

Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung.

Nat Immunol 2020 11 28;21(11):1371-1383. Epub 2020 Sep 28.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Foxp3 regulatory T (T) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether T cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2 T cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. Following allergen exposure, ST2 T cells were activated by IL-33 to suppress IL-17-producing γδ T cells. ST2 signaling in T cells induced Ebi3, a component of the heterodimeric cytokine IL-35 that was required for T cell-mediated suppression of γδ T cells. This response resulted in fewer eosinophil-attracting chemokines and reduced eosinophil recruitment into the lung, which was beneficial to the host in reducing allergen-induced inflammation. Thus, we define a fundamental role for ST2 T cells in the lung as a negative regulator of the early innate γδ T cell response to mucosal injury.
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http://dx.doi.org/10.1038/s41590-020-0785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578082PMC
November 2020

Astrocyte- and Neuron-Derived CXCL1 Drives Neutrophil Transmigration and Blood-Brain Barrier Permeability in Viral Encephalitis.

Cell Rep 2020 09;32(11):108150

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Herpes simplex virus (HSV)-1 encephalitis has significant morbidity partly because of an over-exuberant immune response characterized by leukocyte infiltration into the brain and increased blood-brain barrier (BBB) permeability. Determining the role of specific leukocyte subsets and the factors that mediate their recruitment into the brain is critical to developing targeted immune therapies. In a murine model, we find that the chemokines CXCL1 and CCL2 are induced in the brain following HSV-1 infection. Ccr2 (CCL2 receptor)-deficient mice have reduced monocyte recruitment, uncontrolled viral replication, and increased morbidity. Contrastingly, Cxcr2 (CXCL1 receptor)-deficient mice exhibit markedly reduced neutrophil recruitment, BBB permeability, and morbidity, without influencing viral load. CXCL1 is produced by astrocytes in response to HSV-1 and by astrocytes and neurons in response to IL-1α, and it is the critical ligand required for neutrophil transendothelial migration, which correlates with BBB breakdown. Thus, the CXCL1-CXCR2 axis represents an attractive therapeutic target to limit neutrophil-mediated morbidity in HSV-1 encephalitis.
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http://dx.doi.org/10.1016/j.celrep.2020.108150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548103PMC
September 2020

CD49a Regulates Cutaneous Resident Memory CD8 T Cell Persistence and Response.

Cell Rep 2020 09;32(9):108085

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

CD8 tissue-resident memory T cells (T) persist at sites of previous infection, where they provide rapid local protection against pathogen challenge. CD8 T expressing the α1 chain (CD49a) of integrin VLA-1 have been identified within sites of resolved skin infection and in vitiligo lesions. We demonstrate that CD49a is expressed early following T cell activation in vivo, and TGF-β and IL-12 induce CD49a expression by CD8 T cells in vitro. Despite this rapid expression, CD49a is not required for the generation of a primary CD8 T cell response to cutaneous herpes simplex virus (HSV) infection, migration of CD8 T cells across the epidermal basement membrane, or positioning of T within basal epidermis. Rather, CD49a supports CD8 T persistence within skin, regulates epidermal CD8 T dendritic extensions, and increases the frequency of IFN-γ CD8 T following local antigen challenge. Our results suggest that CD49a promotes optimal cutaneous CD8 T-mediated immunity.
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http://dx.doi.org/10.1016/j.celrep.2020.108085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520726PMC
September 2020

Lung parenchymal and airway changes on CT imaging following allergen challenge and bronchoalveolar lavage in atopic and asthmatic subjects.

Ann Transl Med 2020 Jul;8(14):862

Department of Radiology, Division of Thoracic Imaging and Intervention, Massachusetts General Hospital, Boston, MA, USA.

Background: Computed tomography (CT) imaging findings in the lungs in the setting of an acute allergic response and following bronchoalveolar lavage (BAL) are not well established. Our goals are to characterize the pulmonary CT findings of acute allergic response in both asthmatic and non-asthmatic subjects and, secondarily, to characterize the pulmonary imaging findings following BAL.

Methods: In this prospective observational (cohort) study, we identified atopic, asthmatic (AA) and atopic, non-asthmatic (ANA) subjects. CT of the chest was performed following BAL and instillation of an allergen (AL) and of an inert diluent (DL). Two radiologists analyzed the CT examinations for airway and parenchymal changes.

Results: We had a cohort of 20 atopic subjects (AA=10, ANA=10; F=11, M=9; median age: 23.5 years, range: 18-48 years). Compared to diluent instillation and BAL, allergen instillation resulted in more significant bronchial wall thickening (AL=70%, DL=0%, BAL=0%, P<0.01), consolidations (AL=55%, DL=0%, BAL=15%, P<0.05), and septal thickening (AL=35%, DL=0%, BAL=0%, P<0.01). When present, consolidations tended to be more common in asthmatic subjects compared to non-asthmatics following instillation of the allergen, although this did not reach statistical significance (AA=80% . ANA=30%; P=0.07). BAL, on the other hand, resulted in more ground-glass opacities (BAL=15/20, 75% AL=2/20, 10%, . DL=0/20, 0%; P<0.01).

Conclusions: Acute allergic response in the lungs can result in significant bronchial wall thickening, septal thickening, and consolidations in those with atopy, particularly those with asthma. Localized ground-glass opacities may be expected following BAL, and care should be taken so as to not misinterpret these as significant pathology.
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http://dx.doi.org/10.21037/atm-20-1719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396741PMC
July 2020

Redefining Memory T Cell Subsets.

Trends Immunol 2020 08 6;41(8):645-648. Epub 2020 Jul 6.

Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Divison of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

It has become increasingly clear that the terms used to define memory T cell subsets no longer accurately reflect our understanding of memory T cell biology. Here, we discuss the limitations of our current terminology and propose a new approach for defining memory T cell subsets.
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http://dx.doi.org/10.1016/j.it.2020.06.003DOI Listing
August 2020

Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease.

J Exp Med 2020 09;217(9)

Airway Immunity Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Memory CD4+ T helper type 2 (Th2) cells drive allergic asthma, yet the mechanisms whereby tissue-resident memory Th2 (Th2 Trm) cells and circulating memory Th2 cells collaborate in vivo remain unclear. Using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm cells and circulating memory Th2 cells perform nonredundant functions. Upon HDM rechallenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote eosinophil and CD4+ T cell recruitment. In contrast, Th2 Trm cells proliferated near airways and induced mucus metaplasia, airway hyperresponsiveness, and airway eosinophil activation. Transcriptional analysis revealed that Th2 Trm cells and circulating memory Th2 cells share a core Th2 gene signature but also exhibit distinct transcriptional profiles. Th2 Trm cells express a tissue-adaptation signature, including genes involved in regulating and interacting with extracellular matrix. Our findings demonstrate that Th2 Trm cells and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in promoting allergic airway disease.
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http://dx.doi.org/10.1084/jem.20190865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478729PMC
September 2020

During Aspergillus Infection, Monocyte-Derived DCs, Neutrophils, and Plasmacytoid DCs Enhance Innate Immune Defense through CXCR3-Dependent Crosstalk.

Cell Host Microbe 2020 07 1;28(1):104-116.e4. Epub 2020 Jun 1.

Infectious Disease Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School, New York, NY, USA. Electronic address:

Aspergillus fumigatus, a ubiquitous mold, is a common cause of invasive aspergillosis (IA) in immunocompromised patients. Host defense against IA relies on lung-infiltrating neutrophils and monocyte-derived dendritic cells (Mo-DCs). Here, we demonstrate that plasmacytoid dendritic cells (pDCs), which are prototypically antiviral cells, participate in innate immune crosstalk underlying mucosal antifungal immunity. Aspergillus-infected murine Mo-DCs and neutrophils recruited pDCs to the lung by releasing the CXCR3 ligands, CXCL9 and CXCL10, in a Dectin-1 and Card9- and type I and III interferon signaling-dependent manner, respectively. During aspergillosis, circulating pDCs entered the lung in response to CXCR3-dependent signals. Via targeted pDC ablation, we found that pDCs were essential for host defense in the presence of normal neutrophil and Mo-DC numbers. Although interactions between pDC and fungal cells were not detected, pDCs regulated neutrophil NADPH oxidase activity and conidial killing. Thus, pDCs act as positive feedback amplifiers of neutrophil effector activity against inhaled mold conidia.
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http://dx.doi.org/10.1016/j.chom.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263227PMC
July 2020

Targeting Lymph Node Niches Enhances Type 1 Immune Responses to Immunization.

Cell Rep 2020 05;31(8):107679

Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Generating robust CD4 T-helper cell type 1 (Th1) responses is essential for protective vaccine-induced type 1 immunity. Here, we examine whether immunization formulation associated with enhanced vaccine efficacy promotes antigen targeting and cell recruitment into lymph node (LN) niches associated with optimal type 1 responses. Immunization with antigen and Toll-like receptor agonist emulsified in oil leads to an increased differentiation of IFNγ/TNF-α polyfunctional Th1 cells compared to an identical immunization in saline. Oil immunization results in a rapid delivery and persistence of antigen in interfollicular regions (IFRs) of the LN, whereas without oil, antigen is distributed in the medullary region. Following oil immunization, CXCL10-producing inflammatory monocytes accumulate in the IFR, which mobilizes antigen-specific CD4 T cells into this niche. In this microenvironment, CD4 T cells are advantageously positioned to encounter arriving IL-12-producing inflammatory dendritic cells (DCs). These data suggest that formulations delivering antigen to the LN IFR create an inflammatory niche that can improve vaccine efficacy.
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http://dx.doi.org/10.1016/j.celrep.2020.107679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369031PMC
May 2020

Chemokines in rheumatic diseases: pathogenic role and therapeutic implications.

Nat Rev Rheumatol 2019 12 8;15(12):731-746. Epub 2019 Nov 8.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Chemokines, a family of small secreted chemotactic cytokines, and their G protein-coupled seven transmembrane spanning receptors control the migratory patterns, positioning and cellular interactions of immune cells. The levels of chemokines and their receptors are increased in the blood and within inflamed tissue of patients with rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis or idiopathic inflammatory myopathies. Chemokine ligand-receptor interactions control the recruitment of leukocytes into tissue, which are central to the pathogenesis of these rheumatic diseases. Although the blockade of various chemokines and chemokine receptors has yielded promising results in preclinical animal models of rheumatic diseases, human clinical trials have, in general, been disappointing. However, there have been glimmers of hope from several early-phase clinical trials that suggest that sufficiently blocking the relevant chemokine pathway might in fact have clinical benefits in rheumatic diseases. Hence, the chemokine system remains a promising therapeutic target for rheumatic diseases and requires further study.
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http://dx.doi.org/10.1038/s41584-019-0323-6DOI Listing
December 2019

Migratory DCs activate TGF-β to precondition naïve CD8 T cells for tissue-resident memory fate.

Science 2019 10;366(6462)

Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.

Epithelial resident memory T (eT) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eT cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor β (TGF-β) epigenetically conditions resting naïve CD8 T cells and prepares them for the formation of eT cells in a mouse model of skin vaccination. Naïve T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I-dependent interactions with peripheral tissue-derived migratory dendritic cells (DCs) and depends on DC expression of TGF-β-activating α integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs.
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http://dx.doi.org/10.1126/science.aav5728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939608PMC
October 2019

Monocyte-derived dendritic cells in malaria.

Curr Opin Microbiol 2019 12 19;52:139-150. Epub 2019 Sep 19.

Fundação Oswaldo Cruz - Minas, 30190-002 Belo Horizonte, MG, Brazil; University of Massachusetts Medical School, 01605 Worcester, MA, United States; Plataforma de Medicina Translacional, Fundação Oswaldo Cruz, 14049-900, Ribeirão Preto, SP, Brazil. Electronic address:

The pathogenesis of malaria is a multifactorial syndrome associated with a deleterious inflammatory response that is responsible for many of the clinical manifestations. While dendritic cells (DCs) play a critical role in initiating acquired immunity and host resistance to infection, they also play a pathogenic role in inflammatory diseases. In our recent studies, we found in different rodent malaria models that the monocyte-derived DCs (MO-DCs) become, transiently, a main DC population in spleens and inflamed non-lymphoid organs. These studies suggest that acute infection with Plasmodium berghei promotes the differentiation of splenic monocytes into inflammatory monocytes (iMOs) and thereafter into MO-DCs that play a pathogenic role by promoting inflammation and tissue damage. The recruitment of MO-DCs to the lungs and brain are dependent on expression of CCR4 and CCR5, respectively, and expression of respective chemokine ligands in each organ. Once they reach the target organ the MO-DCs produce the CXCR3 ligands (CXCL9 and CXCL10), recruit CD8 T cells, and produce toxic metabolites that play an important role in the development of experimental cerebral malaria (ECM) and acute respiratory distress syndrome (ARDS).
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http://dx.doi.org/10.1016/j.mib.2019.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981220PMC
December 2019

Dectin-2-induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis.

J Clin Invest 2019 06 6;129(9):3610-3624. Epub 2019 Jun 6.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Environmental triggers, including those from pathogens, are thought to play an important role in triggering autoimmune diseases, such as vasculitis, in genetically susceptible individuals. The mechanism by which activation of the innate immune system contributes to vessel-specific autoimmunity in vasculitis is not known. Systemic administration of Candida albicans water-soluble extract (CAWS) induces vasculitis in the aortic root and coronary arteries of mice that mimics human Kawasaki disease. We found that Dectin-2 signaling in macrophages resident in the aortic root of the heart induced early CCL2 production and the initial recruitment of CCR2+ inflammatory monocytes (iMo) into the aortic root and coronary arteries. iMo differentiated into monocyte-derived dendritic cells (Mo-DC) in the vessel wall and were induced to release IL-1β in a Dectin-2-Syk-NLRP3 inflammasome dependent pathway. IL-1β then activated cardiac endothelial cells to express CXCL1 and CCL2 and adhesion molecules that induced neutrophil and further iMo recruitment and accumulation in the aortic root and coronary arteries. Our findings demonstrate that Dectin-2-mediated induction of CCL2 production by macrophages resident in the aortic root and coronary arteries initiates vascular inflammation in a model of Kawasaki disease, suggesting an important role for the innate immune system in initiating vasculitis.
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http://dx.doi.org/10.1172/JCI123778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715376PMC
June 2019

Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy.

Immunity 2019 06 13;50(6):1498-1512.e5. Epub 2019 May 13.

Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address:

Despite compelling rates of durable clinical responses to programmed cell death-1 (PD-1) blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8 T cell response in tumor-bearing mice treated with anti-PD-1 but were not required for the infiltration of CD8 T cells into tumors. The anti-PD-1-induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103 dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands in murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non-responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.
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http://dx.doi.org/10.1016/j.immuni.2019.04.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527362PMC
June 2019

Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation.

Sci Immunol 2019 05;4(35)

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Chemoattractant-induced arrest of circulating leukocytes and their subsequent diapedesis is a fundamental component of inflammation. However, how tissue-derived chemoattractants are transported into the blood vessel lumen to induce leukocyte entry into tissue is not well understood. Here, intravital microscopy in live mice has shown that the "atypical" complement C5a receptor 2 (C5aR2) and the atypical chemokine receptor 1 (ACKR1) expressed on endothelial cells were required for the transport of C5a and CXCR2 chemokine ligands, respectively, into the vessel lumen in a murine model of immune complex-induced arthritis. Transported C5a was required to initiate C5aR1-mediated neutrophil arrest, whereas transported chemokines were required to initiate CXCR2-dependent neutrophil transdendothelial migration. These findings provide new insights into how atypical chemoattractant receptors collaborate with "classical" signaling chemoattractant receptors to control distinct steps in the recruitment of neutrophils into tissue sites of inflammation.
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http://dx.doi.org/10.1126/sciimmunol.aav5951DOI Listing
May 2019

Introduction: Global positioning by chemokines and other mediators.

Authors:
Andrew D Luster

Immunol Rev 2019 05;289(1):5-8

Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.1111/imr.12763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6701954PMC
May 2019

Quantitative assessment of airway remodelling and response to allergen in asthma.

Respirology 2019 11 7;24(11):1073-1080. Epub 2019 Mar 7.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background And Objective: In vivo evaluation of the microstructural differences between asthmatic and non-asthmatic airways and their functional consequences is relevant to understanding and, potentially, treating asthma. In this study, we use endobronchial optical coherence tomography to investigate how allergic airways with asthma differ from allergic non-asthmatic airways in baseline microstructure and in response to allergen challenge.

Methods: A total of 45 subjects completed the study, including 20 allergic, mildly asthmatic individuals, 22 non-asthmatic allergic controls and 3 healthy controls. A 3-cm airway segment in the right middle and right upper lobe were imaged in each subject immediately before and 24 h following segmental allergen challenge to the right middle lobe. Relationships between optical airway measurements (epithelial and mucosal thicknesses, mucosal buckling and mucus) and airway obstruction (FEV /FVC (forced expiratory volume in 1 s/forced vital capacity) and FEV % (FEV as a percentage of predictive value)) were investigated.

Results: Significant increases at baseline and in response to allergen were observed for all four of our imaging metrics in the asthmatic airways compared to the non-asthmatic airways. Epithelial thickness and mucosal buckling exhibited a significant relationship to FEV /FVC in the asthmatic group.

Conclusion: Simultaneous assessments of airway microstructure, buckling and mucus revealed both structural and functional differences between the mildly asthmatic and control groups, with airway buckling seeming to be the most relevant factor. The results of this study demonstrate that a comprehensive, microstructural approach to assessing the airways may be important in future asthma studies as well as in the monitoring and treatment of asthma.
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http://dx.doi.org/10.1111/resp.13521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732047PMC
November 2019

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload-induced cardiac dysfunction.

JCI Insight 2019 04 4;4(7). Epub 2019 Apr 4.

Department of Immunology and.

Heart failure (HF) is associated in humans and mice with increased circulating levels of CXCL9 and CXCL10, chemokine ligands of the CXCR3 receptor, predominantly expressed on CD4+ Th1 cells. Chemokine engagement of receptors is required for T cell integrin activation and recruitment to sites of inflammation. Th1 cells drive adverse cardiac remodeling in pressure overload-induced cardiac dysfunction, and mice lacking the integrin ligand ICAM-1 show defective T cell recruitment to the heart. Here, we show that CXCR3+ T cells infiltrate the heart in humans and mice with pressure overload-induced cardiac dysfunction. Genetic deletion of CXCR3 disrupts CD4+ T cell heart infiltration and prevents adverse cardiac remodeling. We demonstrate that cardiac fibroblasts and cardiac myeloid cells that include resident and infiltrated macrophages are the source of CXCL9 and CXCL10, which mechanistically promote Th1 cell adhesion to ICAM-1 under shear conditions in a CXCR3-dependent manner. To our knowledge, our findings identify a previously unrecognized role for CXCR3 in Th1 cell recruitment into the heart in pressure overload-induced cardiac dysfunction.
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http://dx.doi.org/10.1172/jci.insight.125527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483643PMC
April 2019

HIV-1 and SIV Infection Are Associated with Early Loss of Lung Interstitial CD4+ T Cells and Dissemination of Pulmonary Tuberculosis.

Cell Rep 2019 02;26(6):1409-1418.e5

Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.

Lung interstitial CD4+ T cells are critical for protection against pulmonary infections, but the fate of this population during HIV-1 infection is not well described. We studied CD4+ T cells in the setting of HIV-1 infection in human lung tissue, humanized mice, and a Mycobacterium tuberculosis (Mtb)/simian immunodeficiency virus (SIV) nonhuman primate co-infection model. Infection with a CCR5-tropic strain of HIV-1 or SIV results in severe and rapid loss of lung interstitial CD4+ T cells but not blood or lung alveolar CD4+ T cells. This is accompanied by high HIV-1 production in these cells in vitro and in vivo. Importantly, during early SIV infection, loss of lung interstitial CD4+ T cells is associated with increased dissemination of pulmonary Mtb infection. We show that lung interstitial CD4+ T cells serve as an efficient target for HIV-1 and SIV infection that leads to their early depletion and an increased risk of disseminated tuberculosis.
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http://dx.doi.org/10.1016/j.celrep.2019.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417097PMC
February 2019

HIV-1 Balances the Fitness Costs and Benefits of Disrupting the Host Cell Actin Cytoskeleton Early after Mucosal Transmission.

Cell Host Microbe 2019 01;25(1):73-86.e5

Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address:

HIV-1 primarily infects T lymphocytes and uses these motile cells as migratory vehicles for effective dissemination in the host. Paradoxically, the virus at the same time disrupts multiple cellular processes underlying lymphocyte motility, seemingly counterproductive to rapid systemic infection. Here we show by intravital microscopy in humanized mice that perturbation of the actin cytoskeleton via the lentiviral protein Nef, and not changes to chemokine receptor expression or function, is the dominant cause of dysregulated infected T cell motility in lymphoid tissue by preventing stable cellular polarization required for fast migration. Accordingly, disrupting the Nef hydrophobic patch that facilitates actin cytoskeletal perturbation initially accelerates systemic viral dissemination after female genital transmission. However, the same feature of Nef was subsequently critical for viral persistence in immune-competent hosts. Therefore, a highly conserved activity of lentiviral Nef proteins has dual effects and imposes both fitness costs and benefits on the virus at different stages of infection.
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http://dx.doi.org/10.1016/j.chom.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456338PMC
January 2019

The Chemokine Receptor CCR8 Promotes the Migration of Dendritic Cells into the Lymph Node Parenchyma to Initiate the Allergic Immune Response.

Immunity 2018 09 28;49(3):449-463.e6. Epub 2018 Aug 28.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address:

The migration of mature dendritic cells (DCs) into the draining lymph node (dLN) is thought to depend solely on the chemokine receptor CCR7. CD301b DCs migrate into the dLN after cutaneous allergen exposure and are required for T helper 2 (Th2) differentiation. We found that CD301b DCs poorly upregulated CCR7 expression after allergen exposure and required a second chemokine signal, mediated by CCR8 on CD301b DCs and its ligand CCL8, to exit the subcapsular sinus (SCS) and enter the lymph node (LN) parenchyma. After allergen exposure, CD169SIGN-R1 macrophages in interfollicular regions produced CCL8, which synergized with CCL21 in a Src-kinase-dependent manner to promote CD301b DC migration. In CCR8-deficient mice, CD301b DCs remained in the SCS and were unable to enter the LN parenchyma, resulting in defective Th2 differentiation. We have defined a CCR8-dependent stepwise mechanism of DC-subset-specific migration through which LN CD169SIGN-R1 macrophages control the polarization of the adaptive immune response.
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http://dx.doi.org/10.1016/j.immuni.2018.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192021PMC
September 2018

Single-Cell RNA Sequencing of Lymph Node Stromal Cells Reveals Niche-Associated Heterogeneity.

Immunity 2018 05 8;48(5):1014-1028.e6. Epub 2018 May 8.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address:

Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters. Included are the established subsets, Ccl19 T-zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19 TRCs, likely including cholesterol-25-hydroxylase cells located at the T-zone perimeter, Cxcl9 TRCs in the T-zone and interfollicular region, CD34 SCs in the capsule and medullary vessel adventitia, indolethylamine N-methyltransferase SCs in the medullary cords, and Nr4a1 SCs in several niches. These data help define how transcriptionally distinct LN SCs support niche-restricted immune functions and provide evidence that many SCs are in an activated state.
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http://dx.doi.org/10.1016/j.immuni.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971117PMC
May 2018

Chemokines: Critical Regulators of Memory T Cell Development, Maintenance, and Function.

Adv Immunol 2018 26;138:71-98. Epub 2018 Mar 26.

Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; Divison of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States. Electronic address:

Memory T cells are central to orchestrating antigen-specific recall responses in vivo. Compared to naïve T cells, memory T cells respond more quickly to cognate peptide:MHC with a shorter lag time for entering the cell cycle and exerting effector functions. However, it is now well established that this enhanced responsiveness is not the only mechanism whereby memory T cells are better equipped than naïve T cells to rapidly and robustly induce inflammation. In contrast to naïve T cells, memory T cells are composed of distinct subsets with unique trafficking patterns and localizations. Tissue-resident memory T cells persist in previously inflamed tissue and function as first responders to cognate antigen reexposure. In addition, a heterogeneous group of circulating memory T cells augment inflammation by either rapidly migrating to inflamed tissue or responding to cognate antigen within secondary lymphoid organs and producing additional effector T cells. Defining the mechanisms regulating T cell positioning and trafficking and how this influences the development, maintenance, and function of memory T cell subsets is essential to improving vaccine design as well as treatment of immune-mediated diseases. In this chapter, we will review our current knowledge of how chemokines, critical regulators of cell positioning and migration, govern memory T cell biology in vivo. In addition, we discuss areas of uncertainty and future directions for further delineating how T cell localization influences memory T cell biology.
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http://dx.doi.org/10.1016/bs.ai.2018.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191293PMC
September 2019

CXCL10 stabilizes T cell-brain endothelial cell adhesion leading to the induction of cerebral malaria.

JCI Insight 2018 04 19;3(8). Epub 2018 Apr 19.

Malaria remains one of the world's most significant human infectious diseases and cerebral malaria (CM) is its most deadly complication. CM pathogenesis remains incompletely understood, hindering the development of therapeutics to prevent this lethal complication. Elevated levels of the chemokine CXCL10 are a biomarker for CM, and CXCL10 and its receptor CXCR3 are required for experimental CM (ECM) in mice, but their role has remained unclear. Using multiphoton intravital microscopy, CXCR3 receptor- and ligand-deficient mice and bone marrow chimeric mice, we demonstrate a key role for endothelial cell-produced CXCL10 in inducing the firm adhesion of T cells and preventing their cell detachment from the brain vasculature. Using a CXCL9 and CXCL10 dual-CXCR3-ligand reporter mouse, we found that CXCL10 was strongly induced in the brain endothelium as early as 4 days after infection, while CXCL9 and CXCL10 expression was found in inflammatory monocytes and monocyte-derived DCs within the blood vasculature on day 8. The induction of both CXCL9 and CXCL10 was completely dependent on IFN-γ receptor signaling. These data demonstrate that IFN-γ-induced, endothelium-derived CXCL10 plays a critical role in mediating the T cell-endothelial cell adhesive events that initiate the inflammatory cascade that injures the endothelium and induces the development of ECM.
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http://dx.doi.org/10.1172/jci.insight.98911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931132PMC
April 2018

Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis.

Nat Commun 2018 04 13;9(1):1461. Epub 2018 Apr 13.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA, 02139, USA.

Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR CXC chemokines. The engineered molecules recognize functional epitopes of ELR CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics.
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http://dx.doi.org/10.1038/s41467-018-03687-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899157PMC
April 2018

The critical role of C5a as an initiator of neutrophil-mediated autoimmune inflammation of the joint and skin.

Semin Immunol 2018 06 27;37:21-29. Epub 2018 Mar 27.

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

The deposition of IgG autoantibodies in peripheral tissues and the subsequent activation of the complement system, which leads to the accumulation of the anaphylatoxin C5a in these tissues, is a common hallmark of diverse autoimmune diseases, including rheumatoid arthritis (RA) and pemphigoid diseases (PDs). C5a is a potent chemoattractant for granulocytes and mice deficient in its precursor C5 or its receptor C5aR1 are resistant to granulocyte recruitment and, consequently, to tissue inflammation in several models of autoimmune diseases. However, the mechanism whereby C5a/C5aR regulates granulocyte recruitment in these diseases has remained elusive. Mechanistic studies over the past five years into the role of C5a/C5aR1 in the K/BxN serum arthritis mouse model have provided novel insights into the mechanisms C5a/C5aR1 engages to initiate granulocyte recruitment into the joint. It is now established that the critical actions of C5a/C5aR1 do not proceed in the joint itself, but on the luminal endothelial surface of the joint vasculature, where C5a/C5aR1 mediate the arrest of neutrophils on the endothelium by activating β integrin. Then, C5a/C5aR1 induces the release of leukotriene B (LTB) from the arrested neutrophils. The latter, subsequently, initiates by autocrine/paracrine actions via its receptor BLT1 the egress of neutrophils from the blood vessel lumen into the interstitial. Compelling evidence suggests that this C5a/C5aR1-LTB/BLT1 axis driving granulocyte recruitment in arthritis may represent a more generalizable biological principle critically regulating effector cell recruitment in other IgG autoantibody-induced diseases, such as in pemphigoid diseases. Thus, dual inhibition of C5a and LTB, as implemented in nature by the lipocalin coversin in the soft-tick Ornithodoros moubata, may constitute a most effective therapeutic principle for the treatment of IgG autoantibody-driven diseases.
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http://dx.doi.org/10.1016/j.smim.2018.03.002DOI Listing
June 2018

Automated segmentation and quantification of airway mucus with endobronchial optical coherence tomography.

Biomed Opt Express 2017 Oct 26;8(10):4729-4741. Epub 2017 Sep 26.

Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

We propose a novel suite of algorithms for automatically segmenting the airway lumen and mucus in endobronchial optical coherence tomography (OCT) data sets, as well as a novel approach for quantifying the contents of the mucus. Mucus and lumen were segmented using a robust, multi-stage algorithm that requires only minimal input regarding sheath geometry. The algorithm performance was highly accurate in a wide range of airway and noise conditions. Mucus was classified using mean backscattering intensity and grey level co-occurrence matrix (GLCM) statistics. We evaluated our techniques in vivo in asthmatic and non-asthmatic volunteers.
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http://dx.doi.org/10.1364/BOE.8.004729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654813PMC
October 2017

LTB and BLT1 in inflammatory arthritis.

Semin Immunol 2017 10;33:52-57

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Inflammatory arthritis, including rheumatoid arthritis (RA), is characterized by infiltration of inflammatory cells into the joints. Biological agents targeting TNF-α and IL-6 dramatically improve RA. However, some RA patients do not respond to current treatments and these broadly active upstream biological agents increase the risk of severe infection. Therefore, there remains a need for other effective and safe treatments for RA. Many studies have implicated that blockade of leukotriene B4 (LTB) and its high affinity receptor BLT1 dramatically suppress arthritis in animal models. In addition, levels of LTB in serum, synovial fluid and synovial tissue are increased in RA patients compared to healthy donors or osteoarthritis patients. These data suggest that LTB and BLT1 likely contribute to the pathogenesis of human RA. However, several clinical trials inhibiting BLT1 in RA were not successful. Our recent data revealed that LTB is a key mediator in a complement, lipid, cytokine and chemokine cascade that first initiates and then sustains neutrophilic inflammation in inflammatory arthritis. These new mechanistic studies suggest novel ways to target the LTB-BLT1 pathway for the treatment of RA and other inflammatory diseases.
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http://dx.doi.org/10.1016/j.smim.2017.09.009DOI Listing
October 2017

Targeting CXCR4-dependent immunosuppressive Ly6C monocytes improves antiangiogenic therapy in colorectal cancer.

Proc Natl Acad Sci U S A 2017 09 12;114(39):10455-10460. Epub 2017 Sep 12.

Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114;

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6C monocytes and not Ly6C monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6C monocytes ( mice), Ly6C monocytes ( mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6C monocytes or neutrophils improved anti-VEGFR2-induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2-induced tumor growth delay but specific depletion of Ly6G neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6C monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.
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http://dx.doi.org/10.1073/pnas.1710754114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625928PMC
September 2017