Atopic dermatitis, or atopic eczema, is an allergic inflammatory skin disease that can lead to broader allergic sensitivities, such as in food allergies and asthma. New findings uncover a new approach to treatment, centered on the gene expression of regulatory T cells, which modulate inflammatory signaling. The recently published work in Science Immunology comes from a Boston Children’s Hospital-led team of researchers.
The condition is caused by the production of type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s), activated T helper 2 (TH2) cells. On the other hand, another type of immune cell, the regulatory T cells (Tregs), are known to communicate with ILC2 and TH2 to mitigate the “type 2” responses, effectively suppressing the allergic response.
Populations of Tregs, however, seem to number the same in eczema lesions and are already generally abundant in the skin compared to the rest of the body. "Our question was, is there something special about the Tregs that reside in the skin?" says senior author Raif Geha.
The team purified Tregs from the skin and blood and compared levels of gene expression. One particularly elevated gene was the transcription factor retinoid-related orphan receptor alpha, or RORα. The team pursued further investigation of this gene in two mouse models.
"We then used a genetic trick to remove RORα only from Tregs," says Geha. "Without RORα, allergic inflammation went crazy in both our mouse models." The team found as much as a three-fold increase in the influx of inflammatory cells―in particular, ILC2s and TH2 cells.
Why, then, did the Tregs stop working when RORα was removed? As it turns out, without RORα, Tregs downregulated a receptor for TL1A, a cytokine released by keratinocytes that activate not just Tregs, but also ILC2 and TH2 effector cells.
"The two kinds of immune cells are competing for TL1A," Geha explains. "If Tregs don't have this receptor, they can't 'see' TL1A. Not only are they not activated, but more TL1A is available to activate the effector cells. So you have a double whammy."
Geha and his team now seek to investigate how RORα is expressed in human eczema with the hope of clinical applications. For instance, topical creams containing RORα agonists may be used to boost the receptor’s anti-inflammatory activity. In addition, the study has shown that RORα regulates other genes involved with Treg function, adding more potential target pathways.