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⇱ Regulation of immunological homeostasis in the respiratory tract | Nature Reviews Immunology

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Key Points

  • The central theme of this Review is how the respiratory immune system maintains a strong defence against incoming pathogens, while avoiding the pathogenic consequences of inappropriate responses to much more frequent exposures to airborne non-pathogenic antigens.

  • The effects of the anatomical organization of the immune system at different levels of the respiratory tract emphasizes the defining immunological features of individual tissue compartments within the conducting airways versus the lung parenchyma.

  • The induction of the immune response in the lungs involves complicated cellular dynamics, in particular involving the control of tissue-specific homing via mechanisms related to the functioning of the common mucosal immune system.

  • Pattern-recognition receptors, including Toll-like receptors, have a central role in local immune surveillance.

  • Individual cell types have specialized roles in maintaining local immunological homeostasis, so it is important to elucidate their nature and function(s). The key players are lung macrophage populations, airway epithelial cells, and in particular dendritic cell (DC) subpopulations and regulatory T cells; natural-killer-cell populations and mast cells are also important.

  • There is an emerging role(s) for T helper 17 (TH17) cells, and 'inflammatory' TH2 cells, for which differentiation is driven via epithelial-cell-derived thymic stromal lymphopoietin signals that act together with DCs.

  • Aspects of the pathogenesis of atopic asthma are an exemplary model of how these overlapping regulatory systems interact to maintain local homeostasis. A classic example is the complex interplay among airway mucosal DCs, adjacent macrophages, incoming recirculating memory TH cells and subsequently recruited regulatory T cells in controlling the intensity and duration of local recall responses to inhaled allergen.

Abstract

The respiratory tract has an approximate surface area of 70 m2 in adult humans, which is in virtually direct contact with the outside environment. It contains a uniquely rich vascular bed containing a large pool of marginated T cells, and harbours a layer of single-cell-thick epithelial tissue through which re-oxygenation of blood must occur uninterrupted for survival. It is therefore not surprising that the respiratory tract is never more than a short step away from disaster. We have only a partial understanding of how immunological homeostasis is maintained in these tissues, but it is becoming clear that the immune system has evolved a range of specific mechanisms to deal with the unique problems encountered in this specialized microenvironment.

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Figure 1: Antigen uptake and migratory patterns for immune induction in the lungs.
The alternative text for this image may have been generated using AI.
Figure 2: A model for antigen sampling at mucosal sites.
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Figure 3: Distribution of DCs and T cells in the tracheal mucosa.
The alternative text for this image may have been generated using AI.
Figure 4: Trafficking of lymphoid cells mediated by specific adhesion molecules and chemokine receptors.
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Acknowledgements

P.G.H. is supported by the National Health and Medical Research Foundation of Australia.

Author information

Authors and Affiliations

  1. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, 6009, Western Australia

    Patrick G. Holt, Deborah H. Strickland & Matthew E. WikstrΓΆm

  2. University of Oslo and Division of Pathology, LIIPAT, Centre for Immune Regulation, Institute of Pathology, Rikshospitalet, N-0027, Oslo, Norway

    Frode L. Jahnsen

Authors
  1. Patrick G. Holt
  2. Deborah H. Strickland
  3. Matthew E. WikstrΓΆm
  4. Frode L. Jahnsen

Corresponding author

Correspondence to Patrick G. Holt.

Glossary

Epithelial cells

Cells that line all tissues and act to protect them by regulating or resisting the passage of exogenous matter.

Secretory goblet cells

Mucus-secreting cells within the airway epithelium.

Plasmacytoid dendritic cells

(pDCs). A population of cells with a plasma-cell-like morphology that produce high levels of type I interferons after exposure to viruses. Human pDCs express high levels of CD123, the interleukin-3 receptor Ξ±-chain, and depend on interleukin-3 as a growth factor.

Lamina propria

Loose connective tissue that is located immediately under the airway epithelium.

Mast cells

A leukocyte population that secretes histamine and other inflammatory mediators on antibody crosslinking of its IgE receptors, and that is largely responsible for acute manifestations of the allergic response.

Plasma cells

Antibody-secreting cells that are generated from antigen-specific B cells.

Anergized cell

A cell that is characterized by its weak response to normal stimuli. An anergized T cell is unable to produce large amounts of interleukin-2 or proliferate vigorously when stimulated via CD3 or its T-cell receptor.

Mucociliary elevator

Upward transport of mucus stream from the lungs by ciliated epithelial cells.

Pattern-recognition receptors

(PRRs). Host receptors (such as Toll-like receptors) that are able to sense pathogen-associated molecular patterns and initiate signalling cascades (involving activation of nuclear factor-ΞΊB) that lead to an innate immune response.

Epidermotropism

Movement towards the epidermis.

Protein-recall antigens

Antigens to which individuals or experimental animals have been previously sensitized.

Inhalation tolerance

The development of immunological tolerance to repeatedly inhaled antigen.

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Holt, P., Strickland, D., WikstrΓΆm, M. et al. Regulation of immunological homeostasis in the respiratory tract. Nat Rev Immunol 8, 142–152 (2008). https://doi.org/10.1038/nri2236

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  • DOI: https://doi.org/10.1038/nri2236

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