Reviews and feature article
T-cell effector pathways in allergic diseases: Transcriptional mechanisms and therapeutic targets

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Originally interpreted within the framework of a binary TH1/TH2 paradigm, our knowledge of the pathogenesis of atopic diseases has broadened to incorporate the contribution of T regulatory cells and the newly described proinflammatory TH17 cell lineage. The commitment of peripheral T-cell clones to undergo differentiation into one of those lineages is shaped by self-reinforcing transcriptional circuitries that center on key transcriptional regulators: T-box expressed in T cells (TH1), GATA-3 (TH2), forkhead box p3 (T regulatory cells), and retinoid-related orphan receptor γτ/retinoid-related orphan receptor α (TH17). These circuits function both to establish the respective lineage phenotype and to enable epigenetic changes that maintain those phenotypes long-term. This evolving view of how signaling and transcriptional networks generate effector T-cell responses suggests novel therapeutic approaches to reprogram effector T-cell lineage commitment in allergic diseases in favor of tolerance induction.

Section snippets

Transcriptional circuits and TH cell phenotype maintenance

The capacity of master regulatory factors to orchestrate TH cell differentiation is critically dependent on the induction by those factors of transcriptional circuits that establish the TH cell phenotype and maintain its stability. They also benefit from epigenetic changes that are brought about by the action of those circuits, and from the modular nature of TF domains, which allow 1 factor to simultaneously mediate interactions with DNA, other TFs, histones, and histone-modifying enzymes.9

Therapeutic strategies of targeting TFs

Transcription factors are the key regulators of immune responses and inflammation. Therefore, pharmacologic approaches of targeting TFs may be used as a strategy to treat diseases in the immune system, such as asthma. The strategies that modify the actions of TFs include direct blocking of their activation, interfering with their expression using nucleic acid–based technologies, and altering their interactions with other TFs.105 Here we present select examples of such approaches.

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    (Supported by an educational grant from Merck & Co., Inc.)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Supported by the National Institute of Allergy and Infectious Diseases–funded University of California at Los Angeles Asthma and Allergic Disease Clinical Research Center (U19 AI070453), a US Environmental Protection Agency (Science to Achieve Results) grant to the Southern California Particle Center, and National Institutes of Health grant 2R01AI065617 (T.A.C.).

    Disclosure of potential conflict of interest: A. E. Nel has served as an expert witness in alleged rate effects of vaccine components and mold litigation. The rest of the authors have declared that they have no conflict of interest.

    Terms in boldface and italics are defined in the glossary on page 813.

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