airway epithelial cells (AECs)

airway surface liquid (ASL),

mucosal‐associated invariant T cells (MAITs)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832344/
Innate defences to Mycobacterium tuberculosis (Mtb) in the airways: The respiratory mucosa

Mtb is inhaled through the nose and mouth and passes along the trachea, bronchus, bronchioles and eventually to the alveoli in the
lung. Along the airway is the respiratory mucosa that forms the first line of defence against Mtb. It consists of (i) the epithelium, a
layer of airway epithelial cells (AECs) forming a barrier that prevents invasion; (ii) the lamina propria, a layer of connective tissue and
immune cells, including lymphocytes and macrophages; and (iii) a coating of a highly complex substance known as airway surface
liquid (ASL), which contains mucus, immunoglobulin A and an array of other innate immune factors on the luminal surface. Also
located in prime positions along the airways to encounter Mtb are bronchial‐ or nasal‐associated lymphoid tissues that are crucial for
Mtb antigen sampling.

AECs can recognize pathogen‐associated molecular patterns (PAMPs) present on Mtb surfaces as they constitutively express pattern
recognition receptors such as Toll‐like receptors, Dectin‐1, C‐type lectin receptors (CLRs), nucleotide‐binding oligomerization
domain‐containing protein 2 (NOD2), dendritic cell (DC)‐specific intercellular adhesion molecule‐3‐grabbing non‐integrin and
mannose receptor. 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) 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. Crucially, AECs control the composition of ASL. ASL contains anti‐microbial
peptides that have been implicated in Mtb resistance, such as β‐defensin, cathelicidin (LL‐37)and hepcidin, as well as a variety of
cytokines and chemokines that are secreted by AECs to recruit and activate phagocytes.

Mtb that successfully passes through the upper airways will be delivered to the alveoli. The alveoli consists of a thin lining of type I
and II epithelial cells as well as other immune cells such as alveolar macrophages (AMs), DCs and neutrophils. Type I epithelial cells
form the walls of the alveolus, and these cells are primarily involved with gas exchange. Whether they can be infected by Mtb
remains to be seen. In contrast, infection of type II epithelial cells by Mtb has been extensively studied in vitro, and Mtb DNA has
been detected within these cells in post‐mortem studies. Similar to AECs, these cells produce anti‐microbial molecules. Additionally,
type II cells produce and secrete pulmonary surfactant, hydrolytic enzymes and hydrolases in the extracellular lining of the lung.
Surfactant proteins (members of the collectin family) bind to Mtb, causing agglutination and enhanced phagocytosis by
macrophages. Secreted hydrolases can alter the cell wall of Mtb and affect interactions with macrophages and host immune
responses.
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https://www.frontiersin.org/articles/10.3389/fimmu.2018.00709/full

Figure 1. Multiple players in Mycobacterium tuberculosis (Mtb) infection and immunity: lung microbiota, lung epithelium, gut–lung axis, gut microbiota, innate and
adaptive lymphocytes. (A) The upper (oro/nasopharyngeal) and lower respiratory (lung) microbiota. (B) Alveolar epithelial cells secrete cytokines, opsonins, and
antimicrobial peptides upon mycobacterial infection. Alveolar macrophages/interstitial macrophages constitute the first line of immune defense and also the first
port of entry during mycobacterial infection, but their interaction with lung microbiota is not yet known. Innate lymphocytes, such as MAIT, NK, NKT, γδ T cells, and
innate lymphoid cells (ILCs) become activated, and their coordination leads to subsequent expansion/modulation of adaptive T and B cells. Dendritic cells
transport Mtb antigens to draining lymph nodes to promote Mtb-specific immunity. (C). In a healthy state, the gut microbiota regulates lung immunity and
influences the lung microbiota. Dysbiosis caused by anti-TB therapy in the gut can lead to dysregulation of immune responses in the lung. (D). The intestinal
microbes and their metabolites regulate ILCs directly, or through cytokines produced by gut epithelium or DCs. ILCs and DCs in turn regulate adaptive T and B cells
in the gut which migrate systemically and to lungs. Also, a combination of signals from microbes leads to migration of DCs to the draining lymph nodes, where DCs
promote activation of various T cell subsets and B cells. During mycobacterial infection, cells activated in gut-associated lymphoid tissue (GALT) and mesenteric
lymph nodes migrate to the lungs where they promote protective immunity and influence the lung microbiota. Bacterial metabolites are also directly transported
to the lungs to influence the lung immunity against mycobacterial infection. The exact pathways of interactions between the components of (A–D) are still being
explored.