Key Points
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GATA-binding protein 3 (GATA3) expression and signal transducer and activator of transcription 5 (STAT5) activation are two key events for TH2 cell differentiation in vitro and possibly in vivo.
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Epithelial cells, dendritic cells and basophils are responsible for sensing allergens and helminth products and thus initiate TH2-type immune responses in vivo.
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Epithelial cells produce the TH2-promoting cytokines thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and IL-33, and basophils produce IL-4, TSLP and IL-25 during the initiation stage of TH2 cell development. These cytokines may have important roles in inducing TH2-type responses, but the relative importance of each cytokine differs among individual models of TH2 cell-associated diseases.
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Both dendritic cells and basophils can serve as TH2-inducing antigen-presenting cells. Although basophils are crucial for some TH2-type responses, they are dispensable in other models where dendritic cells or other potential antigen-presenting cells are involved.
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IL-25 and IL-33 responsive non-B non-T cells produce TH2-associted cytokines, including IL-5 and IL-13, following IL-25 or IL-33 stimulation. These cells can be thought to be innate effector cells during TH2-type responses.
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IL-4, TSLP, IL-25 and IL-33 are also involved in the amplification of the TH2-type responses by affecting several cell types.
Abstract
CD4+ T helper (TH) cells have crucial roles in orchestrating adaptive immune responses. TH2 cells control immunity to extracellular parasites and all forms of allergic inflammatory responses. Although we understand the initiation of the TH2-type response in tissue culture in great detail, much less is known about TH2 cell induction in vivo. Here we discuss the involvement of allergen- and parasite product-mediated activation of epithelial cells, basophils and dendritic cells and the functions of the cytokines interleukin-4 (IL-4), IL-25, IL-33 and thymic stromal lymphopoietin in the initiation and amplification of TH2-type immune responses in vivo.
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The work is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, and the US National Institutes of Health.
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Glossary
- Asthma
-
A chronic disease of the lung, characterized by airway hyperresponsiveness and inflammation. The most common form of the disease, allergicasthma, results from inappropriate immune responses to common allergens in genetically susceptible individuals. Allergic asthma is characterized by infiltration of the airway wall with mast cells, lymphocytes and eosinophils. CD4+ T cells producing TH2-type cytokines are thought to have a crucial role in orchestrating the recruitment and activation of these effector cells of the allergic response.
- Airway hyperresponsiveness
-
Increased narrowing of the airways, initiated by exposure to a defined stimulus that usually has little or no effect on airway function in normal individuals. This is a defining physiological characteristic of asthma.
- Non-B non-T cells
-
(NBNT cells). Cells that are different from basophils, eosinophils, mast cells and NKT cells and can produce IL-5 and IL-13 but little or no IL-4 in response to IL-25 or IL-33 stimulation. They may produce IL-4 in response to phorbol 12-myristate 13-acetate (PMA) plus ionomycin stimulation. These cells were described as MHC class IIhiCD11clowF4/80lowCD4−CD8− or KIT+FcɛRI− or LIN−KIT+SCA1+IL-7Ra+ST2+ in three different reports, and they may comprise three different cell types.
- WNT
-
A signalling mediator named both for its mutant phenotype in Drosophila melanogaster (Wingless) and for its role as a preferential retrovirus integration site in murine leukaemia virus-induced leukaemias (Int-1). WNT signalling activates the T cell factor 1(TCF1) and lymphoid enhancer-binding factor 1 (LEF1) families of transcription factors by stabilizing their co-activator β-catenin and mobilizing it from the cytoplasm to the nucleus.
- Cysteine proteases
-
Enzymes requiring a cysteine thiol in their catalytic pockets to cleave polypeptides by hydrolysis of the peptide bonds. Common cysteine proteases include papain and bromelain.
- β2-microglobulin
-
(β2m). A single immunoglobulin-like domain that non-covalently associates with the main polypeptide chain of MHC class I molecules. In the absence of β2m, MHC class I molecules are unstable and are therefore found at low levels at the cell surface.
- Altered peptide ligands
-
(APLs). Peptide analogues that are derived from the original antigenic peptide. They commonly have amino acid substitutions at TCR-contact residues. TCR engagement by these APLs usually leads to partial or incomplete T cell activation. Antagonistic APLs can specifically antagonize and inhibit T cell activation that is induced by the wild-type antigenic peptide.
- Recombination-activating gene (Rag)-knockout mice
-
Rag1 and Rag2 are expressed by developing lymphocytes. Mice that are deficient in either RAG protein fail to produce B and T cells owing to a developmental block in the gene rearrangement that is required for receptor expression.
- Alternatively activated macrophage
-
A macrophage stimulated by IL-4 or IL-13 that expresses arginase 1, the mannose receptor and IL-4Rα. There may be pathogen-associated molecular patterns expressed by helminths that can also drive the alternative activation of macrophages.
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Paul, W., Zhu, J. How are TH2-type immune responses initiated and amplified?. Nat Rev Immunol 10, 225–235 (2010). https://doi.org/10.1038/nri2735
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DOI: https://doi.org/10.1038/nri2735
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