The role of T regulatory cells in cigarette smoke-induced susceptibility to tuberculosis
The role of T regulatory cells in cigarette smoke-induced susceptibility to tuberculosis
批准号:
9295969
负责人:
EDWARD D CHAN
金额:
$12.14万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-06-14 至 2019-05-31
关键词:
AddressAdoptive TransferAirAlveolar MacrophagesAntitubercular AgentsAutophagocytosisCell surfaceCellsCessation of lifeClinicalCoculture TechniquesCytotoxic T-Lymphocyte-Associated Protein 4Dendritic CellsEpidemiologyFOXP3 geneFoundationsFutureGoalsHomeostasisHumanImmune responseImmune systemImmunologicsImmunosuppressive AgentsImpairmentInterferon Type IIInterleukin-10Laboratory AnimalsLungLymphocyteLysosomesMalignant NeoplasmsMediatingMicrobiologyModelingMusMycobacterium tuberculosisNicotineOutcomePhagosomesPharmacologyPlayPopulationPredisposing FactorPredispositionPulmonary PathologyRecoveryRegulatory T-LymphocyteResistanceRoleSignaling MoleculeSmokelessSmokingTNF geneTh1 CellsTransforming Growth Factor betaTuberculosisUp-RegulationWarcigarette smoke-inducedcigarette smokingcytokineenvironmental tobacco smoke exposureexperimental studyglobal healthimmunoregulationimproved outcomein vivoinhibitor/antagonistmacrophagemouse modelpathogentuberculosis immunitytuberculosis treatment
中文摘要
香烟烟雾(CS)损害宿主对结核分枝杆菌(MTB)的保护性免疫反应。
英文摘要
Cigarette smoke (CS) impairs host-protective immune responses to Mycobacterium tuberculosis (MTB).
However, an overlooked aspect is how CS or nicotine may drive immunosuppressive cells to increase
susceptibility to MTB. T regulatory cells (Tregs) are immunosuppressive cells that predispose laboratory
animals and humans to TB. CS or nicotine not only increases the influx of Tregs to the lungs but also induces
cell surface signaling molecules – programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein
4 (CTLA-4) – that enhance their immunosuppressive activity. Our central hypothesis is that CS enhances the
immunosuppressive function of Tregs via induction of PD-1 and CTLA-4, and that this upregulation of Treg
activity plays a pivotal role in impairing control of MTB infection. We will undertake a two-pronged approach,
using both an in vivo murine model and an ex vivo model using primary human cells. First, we will adoptively
transfer equal number of air- or CS-exposed Tregs into CS-naïve mice and then infect the recipient mice with
MTB to determine if transfer of CS-exposed Tregs aggravates MTB infection more than transfer of air-exposed
Tregs. Second, we will utilize co-cultures of primary human alveolar macrophages (AM) + Tregs with only the
Tregs exposed to medium alone, CS, or nicotine, and pharmacologic antagonists to PD-1 and CTLA-4 to
establish the mechanism by which CS/nicotine increases Treg activity to impair anti-TB immunity.
Aim 1: Establish the role CS-exposed Tregs play in predisposing to MTB in an in vivo murine model.
Hypothesis: We predict that CS-induced upregulation of Treg activity is a pivotal mechanism by which CS
predisposes to MTB. Thus, compared to mice receiving air-exposed Tregs, mice receiving CS-exposed Tregs
will be more susceptible to TB, demonstrated by fewer host-protective M1 macrophages and TH1 cells, greater
burden of MTB, worse lung pathology, and reduced survival. Approach: We will adoptively transfer the same
number of Tregs from air- or CS-exposed donor mice to CS-naïve mice, infect the recipient mice with MTB,
and determine microbiological and immunological outcomes.
Aim 2: Establish the role CS-exposed Tregs play in impairing human AM control of MTB. Hypothesis:
CS or nicotine will increase PD-1 and CTLA-4 expression on Tregs, and in co-cultures with AM, augment the
suppressive effect of Tregs on AM, demonstrated by increased levels of immunosuppressive cytokines,
decreased levels of host-protective cytokines, reduced phagosome-lysosome (P-L) fusion and autophagy, and
greater recovery of MTB. Blocking PD-1 or CTLA-4 will abrogate these effects. Approach: Air-, CS-, or
nicotine-exposed Tregs will be co-cultured with naïve AM, infected with MTB ± inhibitors to PD-1 or CTLA-4,
and analyzed for MTB burden, cytokines, P-L fusion, and autophagy.
This project will clarify the role played by Tregs in mediating CS-induced susceptibility to TB. Findings from
these studies can provide the foundation for developing unique immunomodulatory approaches to treat TB.
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海外基金