Pulmonary mucosal dendritic cells in T-cell activation: implications for TB therapy

The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases.Keywords: DCs r Delayed Th1 immunity r FimH r Mycobacterium r Tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPulmonary mycobacterial infection is mainly caused by Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), and by other slow growing less virulent nontuberculous Correspondence: Dr. Zhou Xing e-mail: xingz@mcmaster.ca mycobacterial (NTM) species including M. avium and M. kasasii. The continuing high global incidence of and death due to tuberculosis infections [1] and the dramatic increase in pulmonary NTM disease globally over the past three decades [2] underscores the need to further understand the complex host immune responses to mycobacterial exposure in order to develop effective prophylactic and therapeutic strategies.Protective immunity against mycobacterial infection requires the presence of a robust adaptive Th1-type response at the site of Eur. J. Immunol. 2014Immunol. . 44: 1375Immunol. -1386 infection. Upon exposure to the bacterium, mycobacteria is taken up by sentinel APCs such as DCs and delivered to the draining lymph node (dLN) [3,4]. On arrival, these APCs present mycobacterial antigen to naive T cells within the dLN, thereby priming the antigen-specific T cells to a Th1 phenotype and stimulating their expansion [5]. The Th1 cells are then recruited back to the site of infection, and the secretion of Th1 cytokines such as IFN-γ by these cells is critical to activation of infected APCs to control bacterial growth [6]. However, one of the defining characteristics of host defense toward mycobacterial patho...

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“…1) [25,26]. In keeping with the initially delayed proinflammatory cytokine and chemokine responses ( Fig.…”

Section: Delayed Innate Cellular Immune Responses In the Lung Followisupporting

confidence: 79%

“…2) [25,26] and its relationship to the appearance of mycobacteria and antigen-specific Th1 cells in the dLN. We found that the significant arrival of CD11c high MHCII high DCs at the dLN was not seen until day 10 postinfection (Fig.…”

Section: Delayed Arrival Of Antigen-bearing DC In Dln Is Associated Wmentioning

confidence: 99%

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

et al. 2014

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“…Because of the anatomic and tissue microenvironment difference, there are some important phenotypic and functional differences between the DC located in the lung and those in the lymphoid tissues such as the spleen (McCormick et al, 2011). The lung can be divided into three major compartments: the airway lumen, the lung interstitium, and the lung vasculature.…”

Section: Respiratory Mucosal Vaccination Strategies Against Intracellmentioning

confidence: 99%

“…iDC are adept at acquiring antigen and migrating to the dLN for T cell priming. It is currently believed that CD11b + DC are less efficient at antigen acquisition and T cell priming but could be an important contributor to cytokine production and activation of memory T cells (McCormick et al, 2011). PM share many of the surface markers that DC express and the question still remains regarding whether PM act as a precursor to other pulmonary APC populations in the airway and interstitium.…”

Section: Respiratory Mucosal Vaccination Strategies Against Intracellmentioning

confidence: 99%

Filling the Immunological Gap

2015

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“…Under noninflammatory conditions, immune surveillance of the airway lumen is passive and mediated primarily by a limited number of intraepithelial dendritic cells (DCs) [37–39]. However, upon the initiation of an inflammatory response, there is a rapid recruitment of DCs to the various lung compartments [37].…”

Section: Initiation Of Innate Immunity In the Lung Following Mtb mentioning

confidence: 99%

Understanding Delayed T-Cell Priming, Lung Recruitment, and Airway Luminal T-Cell Responses in Host Defense against Pulmonary Tuberculosis

Shaler

Horvath

Lai

et al. 2012

Clinical and Developmental Immunology

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Mycobacterium tuberculosis(M.tb), the causative bacterium of pulmonary tuberculosis (TB), is a serious global health concern. Central toM.tbeffective immune avoidance is its ability to modulate the early innate inflammatory response and prevent the establishment of adaptive T-cell immunity for nearly three weeks. When compared with other intracellular bacterial lung pathogens, such asLegionella pneumophila, or even closely related mycobacterial species such asM. smegmatis, this delay is astonishing. Customarily, the alveolar macrophage (AM) acts as a sentinel, detecting and alerting surrounding cells to the presence of an invader. However, in the case ofM.tb,this may be impaired, thus delaying the recruitment of antigen-presenting cells (APCs) to the lung. Upon uptake by APC populations,M.tbis able to subvert and delay the processing of antigen, MHC class II loading, and the priming of effector T cell populations. This delay ultimately results in the deferred recruitment of effector T cells to not only the lung interstitium but also the airway lumen. Therefore, it is of upmost importance to dissect the mechanisms that contribute to the delayed onset of immune responses followingM.tbinfection. Such knowledge will help design the most effective vaccination strategies against pulmonary TB.

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Pulmonary mucosal dendritic cells in T-cell activation: implications for TB therapy

Cited by 11 publications

References 79 publications

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

Filling the Immunological Gap

Understanding Delayed T-Cell Priming, Lung Recruitment, and Airway Luminal T-Cell Responses in Host Defense against Pulmonary Tuberculosis

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