Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection

Abstract

Immune cells of the distal airways serve as "first responders" of host immunity to the airborne pathogen Mycobacterium tuberculosis (Mtb). Mtb infection of cynomolgus macaques recapitulates the range of human outcomes from clinically silent latent tuberculosis infection (LTBI) to active tuberculosis of various degrees of severity. To further advance the application of this model to human studies, we compared profiles of bronchoalveolar lavage (BAL) cells of humans and cynomolgus macaques before and after Mtb infection. A simple gating strategy effectively defined BAL T-cell and phagocyte populations in both species. BAL from Mtb-naive humans and macaques showed similar differential cell counts. BAL T cells of macaques were composed of fewer CD41 cells but more CD81 and CD4 1 CD8 1 double-positive cells than were BAL T cells of humans. The most common mononuclear phagocyte population in BAL of both species displayed coexpression of HLA-DR, CD206, CD11b, and CD11c; however, multiple phagocyte subsets displaying only some of these markers were observed as well. Macaques with LTBI displayed a marked BAL lymphocytosis that was not observed in humans with LTBI. In macaques, the prevalence of specific mononuclear phagocyte subsets in baseline BAL correlated with ultimate outcomes of Mtb infection (i.e., LTBI versus active disease).Overall, these findings demonstrate the comparability of studies of pulmonary immunity to Mtb in humans and macaques. They also indicate a previously undescribed complexity of airway mononuclear phagocyte populations that suggests further lines of investigation relevant to understanding the mechanisms of both protection from and susceptibility to the development of active tuberculosis within the lung.

The End of the Binary Era: Revisiting the Spectrum of Tuberculosis

“…Alveolar macrophages are capable of killing M. tuberculosis soon after infection but these cells are quite heterogeneous in both humans and macaques, with likely variable bactericidal capacity. Specific subsets of alveolar macrophages observed before M. tuberculosis infection were associated with differences in infection outcome (active vs LTBI) (37). Infected macrophages can induce bronchial epithelial cells to express DEFB4 and other antimicrobial effectors that can kill M. tuberculosis directly (36).…”

Mucosal delivery of tuberculosis vaccines: a review of current approaches and challenges

“…These differences complicate model selection and necessitate routine testing of candidate mucosal vaccines in multiple models to support progression to clinical trials. Comparison between bronchoalveolar lavage (BAL) cells in cynomolgous macaques and humans indicated a large degree of similarity between the two species [18]. This, in combination with the ability of these animals to develop both active and latent infection after low-dose M.tb exposure, makes them a good model to study vaccine immunogenicity and efficacy [19].…”

Translational Potential of Therapeutics Targeting Regulatory Myeloid Cells in Tuberculosis

“…The phenotypic and functional diversity of cellular subsets present within the myeloid compartment remains underappreciated and poorly investigated in the context of TB. The complexity of innate phagocytes in the lungs of TB patients is particularly striking, suggesting that detailed characterization is imperative to understanding the mechanisms of TB susceptibility or protection (Silver et al, 2016 ). MDSC, purposed to regulate inflammation, have gained attention due to their central role in prevention of host anti-tumor immunity and subsequent immune escape (Lesokhin et al, 2012 ).…”