The respiratory system consists of the upper respiratory tract (the nasal cavity, pharynx and larynx) and the lower respiratory tract, including the conducting airway (the trachea and bronchi) and the respiratory zone (the alveoli). The composition of the airway, in terms of its constituent epithelial cell types and resident myeloid and lymphoid cell types, depends on its diameter.
Airway cells are the first responders to invading pathogens. They have multiple functions, which include; providing a physical barrier, acting as innate sensors that secrete first-order cytokines and serving as effectors of antimicrobial defences.
Following respiratory infection by viral, bacterial, fungal and protozoan pathogens, type 1 immune responses are engaged. These types of infection are recognized by pattern recognition receptors in sensor cells such as airway epithelial cells, macrophages, dendritic cells and plasmacytoid dendritic cells.
Infection by helminths or inhalation of allergens results in the engagement of the type 2 immune responses. Epithelial cells and mast cells detect the activities of the helminths and allergens, and secrete cytokines that stimulate the next tier of the immune response.
Sensor cells secrete distinctfirst-order cytokines in response to pathogens and activate tissue-resident lymphocytes to secrete second-order cytokines. These cytokines, in turn, activate various types of effector cells to initiate pathogen elimination and tissue repair.
Various internal and external factors can alter the effectiveness of the signals mediated by the sensors and effectors, and can tip the balance away from antimicrobial host defences and towards pathological inflammation. Strategies to improve disease tolerance may be needed to combat infectious diseases in this setting.
The respiratory immune response consists of multiple tiers of cellular responses that are engaged in a sequential manner in order to control infections. The stepwise engagement of effector functions with progressively increasing host fitness costs limits tissue damage. In addition, specific mechanisms are in place to promote disease tolerance in response to respiratory infections. Environmental factors, obesity and the ageing process can alter the efficiency and regulation of this tiered response, increasing pathology and mortality as a result. In this Review, we describe the cell types that coordinate pathogen clearance and tissue repair through the serial secretion of cytokines, and discuss how the environment and comorbidity influence this response.
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The authors would like to thank the Howard Hughes Medical Institute and the US National Institutes of Health (NIH) for their support of research in the laboratory (grants AI054359 and HHSN272201100019C). E.F.F. was supported by funding from the NIH (grants T32 HL007974-11 and K08 AI119139-01). R.D.M. was supported by funding from the NIH (grants T32 AI007019-38 and T32 AI055403) and the Francis Trudeau Trainee Fellowship.
The authors declare no competing financial interests.
- First-order cytokines
A group of cytokines released from the cells that initially sense the presence of a pathogen. These cytokines primarily function to alert tissue-resident lymphoid cell populations in order to coordinate an appropriate immune response to the pathogen.
- Innate lymphoid cells
(ILCs). A group of lymphoid cells that lack B and T cell receptors and are resident in a variety of different organs. They are a major source of second-order cytokines that maintain tissue homeostasis and promote effective microbial clearance.
- Second-order cytokines
A group of cytokines released from tissue-resident lymphoid cells in response to signals from first-order cytokines. These cytokines recruit effector cells, and activate effector and tissue-repair functions to help resolve infections.
- Type 1 immune responses
A group of related immune responses to viruses, bacteria, fungi and protozoa that are characterized by the cytokines interferon-γ, tumour necrosis factor, IL-17 and IL-22. These second-order cytokines are secreted by group 1 innate lymphoid cells, group 3 innate lymphoid cells, natural killer cells, natural killer T cells, innate-like lymphocytes, T helper 1 (TH1) cells and TH17 cells. Effectors also include cytotoxic T cells, which kill infected cells.
- Type 2 immune responses
A group of related immune responses to macroparasites, allergens and certain venoms that are characterized by the cytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13. These second-order cytokines are secreted by group 2 innate lymphoid cells, natural killer T cells, T helper 2 (TH2) cells and TH9 cells.
- Ciliated cells
The predominant cell type in the surface epithelium of the conducting airways. Cilia at the apical surface of these cells beat continuously in a coordinated manner to propel airway mucus towards the mouth and nose, where mucus (and entrapped particles) can be removed via coughing or swallowing.
- Goblet cells
Cells that produce airway mucins, the key components of the protective barrier that impedes pathogen entry into the airway epithelium.
- Club cells
Secretory cells (formerly known as Clara cells) that produce detoxifying and antimicrobial compounds that contribute to defence of the airway mucosa. Club cells have also been reported to function as progenitor cells with the ability to replicate and/or differentiate into ciliated cells.
- Basal cells
These cells function as regional progenitor cells of the airway epithelium and have the ability to proliferate in response to damage and differentiate into other surface epithelial cell types.
- Chronic obstructive pulmonary disease
A group of conditions — including chronic obstructive bronchitis and emphysema — characterized by the pathological limitation of airflow in the airway. It is most often caused by tobacco smoking, but can also be caused by other airborne irritants, such as coal dust, and occasionally by genetic abnormalities, such as α1-antitrypsin deficiency.
- Pattern recognition receptors
(PRRs). Germline-encoded receptors that recognize conserved pathogen-associated molecular patterns and activate signalling cascades that initiate an immune response.
- RIG-I-like receptors
(RLRs). A group of cytosolic pattern recognition receptors comprising retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and LGP2 (also known as DHX58), which recognize viral RNA in infected cells and initiate downstream inflammatory and interferon responses by signalling through mitochondrial antiviral signalling protein (MAVS).
- Plasmacytoid DCs
(pDCs). Specialized sensory cells that express Toll-like receptor 7 (TLR7) and TLR9, and rapidly produce large amounts of type I interferons in response to viral infection.
- Type I interferons
(Type I IFNs). Mammalian type I IFNs comprise IFNα (13 subtypes in humans), IFNβ, IFNκ, IFNδ, IFNε, IFNτ, IFNω and IFNζ. All these cytokines bind to and signal through the receptor consisting of the IFNα/β receptor 1 (IFNAR1)–IFNAR2 dimer and trigger the transcription of genes involved in antiviral defence (which are also known as IFN-stimulated genes).
- Type III IFNs
(Type III interferons). The type III IFNs IFNλ1, IFNλ2 and IFNλ3 are potent antiviral cytokines that are secreted by diverse cell types following pattern recognition receptor-mediated detection of viral infection. Upon binding to the IFNλ receptor (a heterodimer comprising interleukin-28 (IL-28) receptor subunit-α (also known as IFNλR1) and IL-10 receptor subunit-β), these IFNs trigger the transcription of genes involved in antiviral defence (which are also known as IFN-stimulated genes).
Constitutively expressed molecules that are released upon cell membrane rupture and alert the immune system.
(AREG). An epidermal growth factor (EGF)-like protein that promotes epithelial cell growth and tissue repair through EGF receptor signalling. AREG is important for promoting disease tolerance in lung infection models.
- Airway hyperresponsiveness
A pathological state in which narrowing of the conducting airways can be easily triggered. Airway hyperresponsiveness is a diagnostic feature of asthma and contributes to airway obstruction.
- Neutrophil extracellular traps
(NETs). An extracellular mesh of chromatin that contains histones, neutrophil-derived proteases and antimicrobial molecules. NETs are released from neutrophils in certain inflammatory scenarios, and are important for ensnaring and trapping extracellular pathogens.
A family of serine proteases that are primarily expressed by mast cells and released upon degranulation. They can initiate proteolytic degradation of numerous substrates, including IL-33 and the extracellular matrix.
- Disease tolerance
A host strategy for improving disease outcomes by improving tissue repair or reducing the detrimental impact of inflammatory signals.
- Metabolic syndrome
A set of risk factors — including obesity, elevated blood pressure and insulin resistance — that are associated with an increased risk of heart disease, diabetes and other negative clinical outcomes.
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Iwasaki, A., Foxman, E. & Molony, R. Early local immune defences in the respiratory tract. Nat Rev Immunol 17, 7–20 (2017). https://doi.org/10.1038/nri.2016.117
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