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  • Review Article
  • Published:

To respond or not to respond: T cells in allergic asthma

Key Points

  • There has been an epidemic rise in the incidence of atopic disease, including allergic asthma, over the past few decades.

  • CD4+ T helper 2 (TH2) cells are the prime mediators of allergic airway inflammation, including eosinophilia and mucus hypersecretion.

  • TH2-cell driven allergic inflammatory responses in the lung require innate immune signals — for example through the Toll-like receptors (TLRs).

  • The dose of pathogen-associated molecular pattern (PAMP) exposure regulates the induction of TH2- versus TH1-type inflammation.

  • TH1 effector T cells do not prevent and might exacerbate lung inflammatory responses.

  • Various types of CD4+ regulatory T cells have been identified that can limit unwanted adaptive immune responses.

  • The link between decreased exposure to infectious agents in early life and the increased incidence of atopic disease (hygiene hypothesis) may be explained by a failure to generate regulatory T-cell populations.

  • Regulatory T cells have been implicated in suppression of airway inflammation.

  • Innate immune system signals, such as those delivered through TLRs, have an important role both in the generation of adaptive immune responses and regulatory T cells.

Abstract

The incidence of allergic asthma has almost doubled in the past two decades. Numerous epidemiological studies have linked the recent surge in atopic disease with decreased exposure to infections in early childhood as a result of a more westernized lifestyle. However, a clear mechanistic explanation for how this might occur is still lacking. An answer might lie in the presently unfolding story of various regulatory T-cell populations that can limit adaptive immune responses, including T helper 2 (TH2)-cell-mediated allergic airway disease.

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Figure 1: Phenotypic distinctions and differential functions of TH1 and TH2 cells.
Figure 2: Requirement for PAMP exposure to elicit an effector response to inhaled antigen.
Figure 3: Pathways for the natural generation of regulatory T-cell populations.
Figure 4: A schematic of the role of PAMPs in sensitization to allergens.

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Acknowledgements

We would like to thank S. Eisenbarth, D. Piggott and J. Huleatt for their contributions to the manuscript and for thoughtful discussions.

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DATABASES

LocusLink

B7-1

B7-2

B7-H2

CD4

IFN-γ

IL-4

IL-5

IL-10

IL-13

TGF-β

TLR4

Glossary

T HELPER 1/T HELPER 2

(TH1/TH2). Functional subsets of CD4+ T cells that express T-cell receptor-αβ and produce either type-1 cytokines (interferon-γ and other cytokines that support macrophage activation, the generation of cytotoxic T cells and the production of opsonizing antibodies) or type-2 cytokines (interleukin-4 (IL-4), IL-5, IL-13 and other cytokines that support B-cell activation, production of non-opsonizing antibodies, allergic reactions and expulsion of extracellular parasites).

INFLAMMATORY BOWEL DISEASE

A group of conditions, of unknown aetiology, in which the intestinal mucosa is chronically inflammed. Includes Crohn disease and ulcerative colitis.

TYPE I DIABETES

(Insulin-dependent diabetes mellitus). A severe form of diabetes mellitus that is usually of abrupt onset during the first two decades of life and requires insulin therapy. It is characterized by an immune-mediated destruction of pancreatic β cells.

PATHOGEN-ASSOCIATED MOLECULAR PATTERNS

(PAMPs). PAMPs are conserved molecular patterns found in microbial pathogens, but not mammalian cells, including terminally mannosylated compounds, bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA. They are recognized by pattern-recognition receptors, such as the mannose receptor and Toll-like receptors.

TOLL-LIKE RECEPTORS

(TLRs). TLRs are receptors present on mammalian cells, mainly on cells that are involved in the innate or adaptive resistance to pathogens. They are homologous to the Toll-receptor gene family in Drosophila, members of which have important roles in both embryogenesis and defence against infection. TLRs have evolved to recognize pathogen-associated molecular patterns (PAMPs) that are conserved and shared by many microbial pathogens.

ANTERIOR-CHAMBER-ASSOCIATED IMMUNE DEVIATION

(ACAID). Systemic antigen-specific tolerance that develops after inoculation of antigen into the immune-privileged site of the anterior chamber of the eye.

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Herrick, C., Bottomly, K. To respond or not to respond: T cells in allergic asthma. Nat Rev Immunol 3, 405–412 (2003). https://doi.org/10.1038/nri1084

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