Abstract
Mycobacterium tuberculosis-specific (M. tuberculosis-specific) T cell responses associated with immune control during asymptomatic latent tuberculosis infection (LTBI) remain poorly understood. Using a nonhuman primate aerosol model, we studied the kinetics, phenotypes, and functions of M. tuberculosis antigen-specific T cells in peripheral and lung compartments of M. tuberculosis-infected asymptomatic rhesus macaques by longitudinally sampling blood and bronchoalveolar lavage, for up to 24 weeks postinfection. We found substantially higher frequencies of M. tuberculosis-specific effector and memory CD4+ and CD8+ T cells producing IFN-γ in the airways compared with peripheral blood, and these frequencies were maintained throughout the study period. Moreover, M. tuberculosis-specific IL-17+ and IL-17+IFN-γ+ double-positive T cells were present in the airways but were largely absent in the periphery, suggesting that balanced mucosal Th1/Th17 responses are associated with LTBI. The majority of M. tuberculosis-specific CD4+ T cells that homed to the airways expressed the chemokine receptor CXCR3 and coexpressed CCR6. Notably, CXCR3+CD4+ cells were found in granulomatous and nongranulomatous regions of the lung and inversely correlated with M. tuberculosis burden. Our findings provide insights into antigen-specific T cell responses associated with asymptomatic M. tuberculosis infection that are relevant for developing better strategies to control TB.
Highlights
After close contact with a person with active tuberculosis (TB), only a minority of individuals develop primary TB disease
Our findings provide insights into antigenspecific T cell responses associated with asymptomatic M. tuberculosis infection that are relevant for developing better strategies to control TB
These results highlight the heterogeneity of clinically asymptomatic animals that control M. tuberculosis infection, consistent with the idea that asymptomatic latent TB infection (LTBI) is represented by a spectrum of M. tuberculosis infection states [3, 5]
Summary
After close contact with a person with active tuberculosis (TB), only a minority of individuals develop primary TB disease. The majority of individuals successfully control Mycobacterium tuberculosis (M. tuberculosis) infection in a clinically asymptomatic state termed latent TB infection (LTBI) [1]. Individuals with LTBI are defined as having a positive tuberculin skin test (TST) and/or Interferon-gamma Release Assay (IGRA), a normal chest radiograph, and the absence of clinical signs and symptoms of disease [2]. Infected individuals are generally thought to contain M. tuberculosis within granulomatous lesions in the lung without completely eradicating bacteria, direct evidence for the persistence of M. tuberculosis in human LTBI is lacking. Identifying immune responses associated with asymptomatic M. tuberculosis infection states will provide key insights into mechanisms of immune control that protect against progressing to active TB disease
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