Lung Neutrophils Facilitate Activation of Naive Antigen-Specific CD4+ T Cells during Mycobacterium tuberculosis Infection

Division of Infectious Diseases, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2011; 186(12):7110-9. DOI: 10.4049/jimmunol.1100001
Source: PubMed


Initiation of the adaptive immune response to Mycobacterium tuberculosis occurs in the lung-draining mediastinal lymph node and requires transport of M. tuberculosis by migratory dendritic cells (DCs) to the local lymph node. The previously published observations that 1) neutrophils are a transiently prominent population of M. tuberculosis-infected cells in the lungs early in infection and 2) that the peak of infected neutrophils immediately precedes the peak of infected DCs in the lungs prompted us to characterize the role of neutrophils in the initiation of adaptive immune responses to M. tuberculosis. We found that, although depletion of neutrophils in vivo increased the frequency of M. tuberculosis-infected DCs in the lungs, it decreased trafficking of DCs to the mediastinal lymph node. This resulted in delayed activation (CD69 expression) and proliferation of naive M. tuberculosis Ag85B-specific CD4 T cells in the mediastinal lymph node. To further characterize the role of neutrophils in DC migration, we used a Transwell chemotaxis system and found that DCs that were directly infected by M. tuberculosis migrated poorly in response to CCL19, an agonist for the chemokine receptor CCR7. In contrast, DCs that had acquired M. tuberculosis through uptake of infected neutrophils exhibited unimpaired migration. These results revealed a mechanism wherein neutrophils promote adaptive immune responses to M. tuberculosis by delivering M. tuberculosis to DCs in a form that makes DCs more effective initiators of naive CD4 T cell activation. These observations provide insight into a mechanism for neutrophils to facilitate initiation of adaptive immune responses in tuberculosis.

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    • "The role that neutrophils play during TB infection is controversial. Previous reports have identified an increased susceptibility (Pedrosa et al., 2000; Seiler et al., 2000) and a delayed initiation of adaptive immunity following depletion of neutrophils (Blomgran and Ernst, 2011), although other studies have ascribed a damaging role in which neutrophils mediate substantial immunopathology (Major et al., 2013; Marzo et al., 2014; Subbian et al., 2013). Neutrophils might indeed play an important early role transporting antigen to the draining lymph nodes and providing warning signals to dendritic cells through the uptake of apoptotic debris containing viable M. tuberculosis bacilli (Alemán et al., 2007; Davis and Ramakrishnan, 2009). "
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    ABSTRACT: Pulmonary tuberculosis (TB) is caused by Mycobacterium tuberculosis in susceptible humans. Here, we infected Diversity Outbred (DO) mice with ∼100 bacilli by aerosol to model responses in a highly heterogeneous population. Following infection, Supersusceptible, Susceptible, and Resistant phenotypes emerged. TB disease (reduced survival, weight loss, high bacterial load) correlated strongly with neutrophils, neutrophil chemokines, Tumor Necrosis Factor (TNF) and cell death. In contrast, immune cytokines were weak correlates of disease. We next applied statistical and machine learning approaches to our dataset of cytokines and chemokines from lungs and blood. Six lung molecules: TNF, CXCL1, CXCL2, CXCL5, Interferon-γ (IFN-γ), Interleukin (IL)-12; and two blood molecules IL-2 and TNF, were identified as important by both statistical and machine learning methods. Using molecular features to generate tree classifiers, CXCL1, CXCL2, and CXCL5 discriminated four classes (Supersusceptible, Susceptible, Resistant, and Non-infected) from each other with approximately 77% accuracy using completely independent experimental data. In contrast, models based on other molecules were less accurate. Low to no IFN-γ, IL-12, IL-2, and IL-10 successfully discriminated Non-infected mice from infected mice, but failed to discriminate disease status amongst Supersusceptible, Susceptible, and Resistant M. tuberculosis infected DO mice. Additional analyses identified CXCL1 as a promising peripheral biomarker of disease and of CXCL1 production in the lungs. From these results, we conclude that: 1) DO mice respond variably to M. tuberculosis infection and will be useful to identify pathways involving necrosis and neutrophils; 2) Data from DO mice is suited for machine learning methods to build, validate, and test models with independent data based solely on molecular biomarkers; 3) Low immunological cytokines best indicate no exposure to M. tuberculosis but cannot distinguish infection from disease. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Jul 2015 · Disease Models and Mechanisms
    • "Because most innate effector cell types are infected with Mtb, it is possible that multiple cell types contribute either directly or indirectly to the delivery of bacteria to the lymph node. For example, depletion of neutrophils decreases the migration of dendritic cells to the lymph node and delays the priming of CD4 T-cell responses (Blomgran and Ernst 2011). Moreover, infection of mice with a nuoG mutant Mtb that cannot suppress neutrophil apoptosis leads to more rapid trafficking of bacteria to the lymph nodes and CD4 T-cell priming (Blomgran et al. 2012). "
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    ABSTRACT: Host resistance to Mycobacterium tuberculosis (Mtb) infection requires the coordinated efforts of innate and adaptive immune cells. Diverse pulmonary myeloid cell populations respond to Mtb with unique contributions to both host-protective and potentially detrimental inflammation. Although multiple cell types of the adaptive immune system respond to Mtb infection, CD4 T cells are the principal antigen-specific cells responsible for containment of Mtb infection, but they can also be major contributors to disease during Mtb infection in several different settings. Here, we will discuss the role of different myeloid populations as well as the dual nature of CD4 T cells in Mtb infection with a primary focus on data generated using in vivo cellular immunological studies in experimental animal models and in humans when available. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    No preview · Article · Jul 2015 · Cold Spring Harbor Perspectives in Medicine
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    • "Neutrophils are involved in the formation of granuloma (Seiler et al., 2003) and in the initiation of T cell response: they were shown to transport live mycobacteria from peripheral tissues to the lymphoid organs and to deliver mycobacterial antigens to DC in a form that makes DC more effective initiators of naïve CD4 + T cell activation (Abadie et al., 2005; Blomgran et al., 2011). "

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