Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection

Sia, Jonathan Kevin; Bizzell, Erica; Madan-Lala, Ranjna; Rengarajan, Jyothi

doi:10.1371/journal.ppat.1006530

Cited by 55 publications

(82 citation statements)

References 57 publications

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“…Our results indicate that both IFN-γ single-positive and IFN-γ+IL-17+ double-positive cells emerge soon after Mtb infection and persist for several weeks, thus likely contributing to controlling Mtb infection during LTBI. These data support and extend previous studies in mice (50, 55, 56) and in macaques (28, 53) suggesting that balanced Th 1 and Th 17 responses are associated with enhanced immunity to TB. Future studies that selectively deplete IL-17 or IFN-γ + CD4 T cells in the context of LTBI or vaccination in macaques will provide more direct evidence for the role of these cells in LTBI.…”

Section: Discussionsupporting

confidence: 91%

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Shanmugasundaram

Bucşan

Ganatra

et al. 2020

Preprint

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27Mycobacterium tuberculosis (Mtb)-specific T cell responses associated with immune control 28 during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a non-29 human primate (NHP) aerosol model, we studied the kinetics, phenotypes and functions of Mtb 30 antigen-specific T cells in peripheral and lung compartments of Mtb-infected asymptomatic 31 rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage (BAL), for up to 32 24 weeks post-infection. We found significantly higher frequencies of Mtb-specific effector and 33 memory CD4 and CD8 T cells producing IFN-γ in the airways compared to peripheral blood, 34 which were maintained throughout the study period. Moreover, Mtb-specific IL-17+ and IL-35 17/IFN-γ double-positive T cells were present in the airways but were largely absent in the 36 periphery, suggesting that balanced mucosal Th 1 /Th 17 responses are associated with LTBI. The 37 majority of Mtb-specific CD4 T cells that homed to the airways expressed the chemokine 38 receptor CXCR3 and co-expressed CCR6. Notably, CXCR3+CD4+ cells were found in 39 granulomatous and non-granulomatous regions of the lung and inversely correlated with Mtb 40 burden. Our findings provide novel insights into antigen-specific T cell responses associated 41 with asymptomatic Mtb infection that are relevant for developing better strategies to control TB. 42 43 46 51 (LTBI)(1). Individuals with LTBI are defined as having a positive tuberculin skin test (TST) 52 and/or Interferon-gamma Release Assay (IGRA), a normal chest radiograph and the absence of 53 clinical signs and symptoms of disease(2). Latently-infected individuals are generally thought to 54 contain Mtb within granulomatous lesions in the lung without completely eradicating bacteria, 55 although direct evidence for the persistence of Mtb in human LTBI is lacking. Moreover, it is 56 increasingly recognized that clinically asymptomatic individuals likely reflect a spectrum of 57 infection outcomes, ranging from individuals who may have eliminated infection, to those with 58 low levels of replicating or non-replicating persistent bacteria, to individuals who may harbor 59 actively replicating bacteria without exhibiting overt clinical symptoms(3-5). Identifying immune 60 responses associated with asymptomatic Mtb infection states will provide key insights into 61 mechanisms of immune control that protect against progressing to active TB disease. 62 63 Antigen-specific T cell responses are critical for immune control of Mtb infection. In response to 64 Mtb infection, the majority of infected people mount robust CD4 T cell responses involving T 65 helper 1 (Th 1 ) cytokines such as IFN-γ and TNF-α, which are important for activating 66 macrophages and curtailing Mtb replication in the lung(6, 7). In addition, IL-17 and Th 17 67 responses have emerged as important for protective immunity against TB, but mucosal Mtb-68 specific Th 17 responses during immune control of LTBI in humans remain poorly studied. In 69 general, the na...

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Section: Discussionsupporting

confidence: 91%

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Shanmugasundaram

Bucşan

Ganatra

et al. 2020

Preprint

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“…HIV and Mtb coinfected human DCs showed reduced expression of costimulatory molecules CD40, CD80 and CD86 as well as pro-inflammatory IL-6, IL-1b and TNF-a, resulting in an impairment to stimulate IFN-c production by CD4 + T cells [155]. In line with these findings, it was recently demonstrated that CD40dependent co-stimulation of DCs was crucial to initiate protective Th17 responses in TB [156]. Qualitative changes in cytokine expression involving reduced Th1 responses have previously been demonstrated in PBMCs from TB/HIV co-infected patients [157,158].…”

Section: Tb/hiv Co-infectionmentioning

confidence: 71%

Friends and foes of tuberculosis: modulation of protective immunity

Brighenti

Joosten

2018

J Intern Med

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Protective immunity in tuberculosis (TB) is subject of debate in the TB research community, as this is key to fully understand TB pathogenesis and to develop new promising tools for TB diagnosis and prognosis as well as a more efficient TB vaccine. IFN-γ producing CD4 T cells are key in TB control, but may not be sufficient to provide protection. Additional subsets have been identified that contribute to protection such as multifunctional and cytolytic T-cell subsets, including classical and nonclassical T cells as well as novel innate immune cell subsets resulting from trained immunity. However, to define protective immune responses against TB, the complexity of balancing TB immunity also has to be considered. In this review, insights into effector cell immunity and how this is modulated by regulatory cells, associated comorbidities and the host microbiome, is discussed. We systematically map how different suppressive immune cell subsets may affect effector cell responses at the local site of infection. We also dissect how common comorbidities such as HIV, helminths and diabetes may bias protective TB immunity towards pathogenic and regulatory responses. Finally, also the composition and diversity of the microbiome in the lung and gut could affect host TB immunity. Understanding these various aspects of the immunological balance in the human host is fundamental to prevent TB infection and disease.

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“…Mucosal administration of DCs has been utilized to assess early antigen-specific T cell responses to mycobacteria in the lungs of mice (12), and antigen-loaded DCs have previously been shown to confer protection against Mtb challenge (9, 13–15). Therefore, we used a tractable DC intratracheal instillation model to assess antigen-specific CD4 T cell responses in vivo following transfer of BCG or BCGΔ hip1 -infected DCs, or control uninfected DCs, into the lungs of mice.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, our studies suggest that deleting BCG hip1 alone, or in concert with deleting additional immune evasion genes, is a feasible approach to enhance DC functions for the rational improvement of BCG as a vaccine. A growing number of studies indicate that vaccination through the mucosal route induces robust antigen-specific responses that confer better protection at mucosal surfaces, such as the lung, relative to parenteral routes (9, 13, 14, 43–48). Using an intratracheal DC installation model, we observed that transfer of DCs infected with BCGΔ hip1 into mouse lungs more effectively activated CD4 T cells, induced higher numbers of antigen-specific mucosal CD4 T cells secreting IFN-γ, IL-2, TNF-α, and IL-17 in vivo, and led to enhanced Mtb control after challenge compared to transfer of BCG-DCs.…”

Section: Discussionmentioning

confidence: 99%

“…For heat-killed BCG infections, bacteria suspended in DMEM/F-12 medium containing 10% FBS, 2mM L-glutamine, and 5% LCM were added to differentiated BMDMs in 24 well plates at indicated MOIs. Murine bone marrow derived dendritic cells (BMDCs) were generated as previously described (9). Bone marrow cells isolated from C57BL/6J mice were grown and differentiated for 8 days in Roswell Park Memorial Institute (RPMI) medium (Lonza, Walkersville, MD) supplemented with 10% FBS (HyClone, Logan, UT), 2mM L-glutamine (Gibco, Grand Island, NY), 20ng/ml recombinant murine granulocyte-macrophage colony-stimulatign factor (rmGM-CSF) (R&D systems, Minneapolis, MN), 50 μM beta-mercaptoethanol (Gibco, Grand Island, NY), 1X non-essential amino acids (Gibco, Grand Island, NY), 10mM HEPES buffer (Lonza, Walkersville, MD), 1mM sodium pyruvate (Lonza, Walkersville, MD).…”

Section: Methodsmentioning

confidence: 99%

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Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses

Bizzell

Sia

Quezada

et al. 2017

Journal of Leukocyte Biology

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Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses to pathogens. Mycobacterium tuberculosis (Mtb) harbors immune evasion mechanisms that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine strain Mycobacterium bovis Bacille Calmette-Guérin (BCG) shares many of the immune evasion proteins utilized by Mtb, but the role of these proteins in DC and T cell responses elicited by BCG is poorly understood. We previously reported that the Mtb serine protease, Hip1, promotes sub-optimal DC responses during infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions and prevents optimal antigen-specific CD4 T cell responses that limit the immunogenicity of BCG. We generated a strain of BCG lacking hip1 (BCGΔhip1) and show that it has superior capacity to induce DC maturation and cytokine production compared with the parental BCG. Furthermore, BCGΔhip1-infected DCs were more effective at driving the production of IFN-γ and IL-17 from antigen-specific CD4 T cells in vitro. Mucosal transfer of BCGΔhip1-infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGΔhip1-infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared with the transfer of BCG-infected DCs. These results reveal that BCG employs Hip1 to impair DC activation, leading to attenuated lung CD4 T cell responses with limited capacity to control Mtb burden after challenge.

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Engaging the CD40-CD40L pathway augments T-helper cell responses and improves control of Mycobacterium tuberculosis infection

Cited by 55 publications

References 57 publications

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Control of Mycobacterium tuberculosis Infection in Lungs is Associated with Recruitment of Antigen-Specific Th1 and Th17 cells Co-expressing CXCR3 and CCR6

Friends and foes of tuberculosis: modulation of protective immunity

Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses

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