T helper 2 (TH2) cells respond to a variety of environmental cues, either directly or indirectly through interaction with cells of the innate immune system. For instance, certain specialized dendritic cells (DCs) promote TH2 cell induction, whereas other DC subsets are suppressive.
Epithelial cell-derived cytokines, such as IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), and IL-4-producing immune cells, such as innate lymphoid cells and basophils, can potentiate TH2 cell responses. However, the relative importance of these innate cell stimuli for TH2 cell development remains to be determined and is likely to be dependent on local environmental cues.
TH2 cell differentiation is fundamentally dependent on the mechanistic target of rapamycin-mediated metabolic transition from oxidative phosphorylation to aerobic glycolysis.
TH cell subsets are somewhat heterogeneous in terms of their cytokine secretion and transcription factor profiles. Single-cell technologies promise to deliver new insight into how TH cells integrate diverse environmental cues to ensure their adaptability during homeostasis, protective immunity and tissue repair.
Our evolving knowledge of TH2 cell differentiation at the molecular and cellular levels has led to the development of novel therapies targeting specific transcription factors and TH2 cell-associated cytokines.
T helper 2 (TH2) cells orchestrate protective type 2 immune responses, such as those that target helminths and facilitate tissue repair, but also contribute to chronic inflammatory diseases, such as asthma and allergy. Here, we review recent insights into how diverse molecular signals from cellular sources, including dendritic cells, innate lymphoid cells and the epithelium, are integrated by T cells to guide the transcriptional and epigenetic changes necessary for TH2 cell differentiation. Our improved understanding of these pathways has opened new avenues for therapeutically targeting TH2 cells in asthma and allergy. The advent of comprehensive single-cell transcriptomics along with improvements in single-cell proteomics and the generation of novel in vivo cell fate mapping techniques promise to expand our understanding of T cell diversity and offer new insight into disease-related heterogeneity and plasticity of TH cell responses.
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The authors apologize to their colleagues whose excellent work they were unable to include due to space limitations. The authors are grateful to P. Fallon and J. Barlow for their thoughtful and insightful suggestions. J.A.W. and A.N.J.M. are funded by the Wellcome Trust (100963/Z/13/Z) and the Medical Research Council (U105178805).
A.N.J.M. has received grant funding from GlaxoSmithKline and MedImmune.
- Innate lymphoid cell
(ILC). A cytokine-producing lymphocyte that, unlike T and B cells, does not express an antigen-specific receptor.
The process through which cells extract membrane fragments from neighbouring cells and exhibit them on their own surface membrane.
- TH2 cytokine locus
The gene locus that harbours the genes encoding the cytokines IL-4, IL-5 and IL-13.
A protein that binds to specific nuclear localization sequences to facilitate the transport of other proteins into the nucleus.
- In vitro-induced Treg (iTreg) cells
Regulatory T cells that can be induced in vitro from naive CD4+ T cells in the presence of transforming growth factor-β (TGFβ).
Distinct subtypes of a disease.
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Walker, J., McKenzie, A. TH2 cell development and function. Nat Rev Immunol 18, 121–133 (2018). https://doi.org/10.1038/nri.2017.118
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