Human Lung Epithelial Cells Contain Mycobacterium tuberculosis in a Late Endosomal Vacuole and Are Efficiently Recognized by CD8+ T Cells

Abstract

Mycobacterium tuberculosis (Mtb) is transmitted via inhalation of aerosolized particles. While alveolar macrophages are thought to play a central role in the acquisition and control of this infection, Mtb also has ample opportunity to interact with the airway epithelium. In this regard, we have recently shown that the upper airways are enriched with a population of non-classical, MR1-restricted, Mtb-reactive CD8+ T cells (MAIT cells). Additionally, we have demonstrated that Mtb-infected epithelial cells lining the upper airways are capable of stimulating IFNγ production by MAIT cells. In this study, we demonstrate that airway epithelial cells efficiently stimulate IFNγ release by MAIT cells as well as HLA-B45 and HLA-E restricted T cell clones. Characterization of the intracellular localization of Mtb in epithelial cells indicates that the vacuole occupied by Mtb in epithelial cells is distinct from DC in that it acquires Rab7 molecules and does not retain markers of early endosomes such as Rab5. The Mtb vacuole is also heterogeneous as there is a varying degree of association with Lamp1 and HLA-I. Although the Mtb vacuole shares markers associated with the late endosome, it does not acidify, and the bacteria are able to replicate within the cell. This work demonstrates that Mtb infected lung epithelial cells are surprisingly efficient at stimulating IFNγ release by CD8+ T cells.

The innate immune response in human tuberculosis

“…These receptors have been implicated in Mtb infection in human AECs and mediate the production of cytokines and effector molecules to mount an effective immune response. AECs play a role as immune sentinels after exposure to Mtb by presenting antigen to mucosal‐associated invariant T cells (MAITs) (Harriff et al ., 2014) and stimulating them to produce interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α and granzyme, factors that may contribute to Mtb clearance. MAIT cells rapidly respond to infection, providing an early IFN‐γ boost to activate macrophages (Gold et al ., 2010).…”

Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis

“…The increased number of IL-32-positive cells in the TB lungs reflects the large number of epithelioid macrophages in the inflammatory and granulomatous responses. Because airway epithelial cells are innate immune cells capable of killing mycobacteria through phagocytosis and elaboration of antimicrobial peptides as well as stimulating IFNγ release by CD8 + T cells (28), it is plausible that increased expression of IL-32 in these cells also reflects a host-protective immune response against MTB. Montoya et al recently showed in human macrophages that IL-32 promoted the production of both defensin-B and cathelicidin, antimicromial peptides with anti-MTB activity (29).…”

Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs

“…However, emerging evidence indicates that the cells of the innate immune system are equipped with "epigenetic memory" where genes encoding specific host defence molecules increase the response upon re-stimulation [4][5][6][7] . Recent studies further demonstrated that airway epithelial cells (AECs) harbour Mycobacterium tuberculosis (Mtb) and are critical during the progression to active disease [8,9] . These cells could thus be important for both host defence and vaccine development, but a more comprehensive knowledge of direct interaction between AECs and mycobacteria is currently lacking [10] .…”