Editors' ChoiceImmunotherapy

Drugging immune regulation

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Science Translational Medicine  10 Jun 2015:
Vol. 7, Issue 291, pp. 291ec97
DOI: 10.1126/scitranslmed.aac5097

A T cell faces a crucial cell fate decision as it develops—a naïve CD4+ T cell can become either an effector T cell that promotes tissue inflammation or a regulatory T cell that suppresses inflammation. The balance between proinflammatory and regulatory T cells is critical to human health; impaired regulatory T cell differentiation and function contribute to the development of autoimmune diseases. Khor and colleagues screened for small molecules that prod naïve cells toward a regulatory T cell identity. The hits from the screen are potential lead compounds for treatment of autoimmune diseases and reveal a new pathway controlling regulatory T cell development.

The authors established an arrayed screening platform to search for small molecules that affect the fate of naïve T cells, measuring the effect of each compound on protein signatures of effector and regulatory T cells. A screen of 3281 FDA-approved small molecules and tool compounds identified a host of chemicals that enhanced regulatory T cell differentiation under in vitro conditions not otherwise conducive to the development of these cells. In addition to confirming some previously reported compounds, the screen also hit on 14 new molecules that selectively boosted regulatory T cells. Harmine—a small molecule hit that stood out because of its structural novelty—promoted development of bona fide regulatory T cells that effectively suppressed inflammation in vitro and in vivo. Intranasal treatment with harmine limited airway inflammation in a mouse model of asthma. These studies highlight harmine as a potential lead compound to instruct the development of future small-molecule therapies for human autoimmune diseases. Furthermore, several targets have been reported for harmine, including dual-specificity tyrosine-phosphorylation regulated kinases (DYRKs). The effects of harmine pointed the authors towards DYRK1A, which turned out to be a new molecular switch controlling T cell fate.

This study demonstrates the power of small molecules to modulate immune cell fate. Small molecules may have pleiotropic effects—influencing multiple pathways—so a specific target protein will not always be identifiable. Nonetheless, chemical biology is proving to be a powerful and unbiased approach that can combine with transcriptomic, proteomic, and genetic studies to identify molecular targets essential for immune regulation.

B. Khor et al., The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. eLife 10.7554/eLife.05920 (2015). [Full Text]

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