TL1A Priming Induces a Multi-Cytokine Th9 Cell Phenotype That Promotes Robust Allergic Inflammation in Murine Models of Asthma

Abstract

The TNF superfamily member TL1A is a costimulatory molecule that signals through its receptor DR3 on T lymphocytes. The Th9 subset of T lymphocytes secretes the pleiotropic cytokine IL-9 which has functions in allergic airway disease, helminth infections, and tumor immunity. TL1A increases IL-9 production from Th9 cells. However, its role in regulating other functions of Th9 cells is unknown. Here we demonstrate that TL1A increases expression of IL-9 and IL-13 as well as the frequency of IL-9 and IL-13 co-expressing cells in murine Th9 cell cultures, inducing a robust multi-cytokine phenotype. Mechanistically, this is linked to histone modifications allowing for increased accessibility at the Il9 and Il13 loci. We further show that TL1A alters the transcription factor network underlying expression of IL-9 and IL-13 in Th9 cells and increases binding of these transcription factors to Il9 and Il13 loci. IL-9 and IL- 13 expression have been well studied in the context of allergic airway disease (AAD) and both have been shown to exacerbate AAD. We demonstrate that TL1A-priming enhances pathogenicity of Th9 cells in murine models of AAD and that this is largely mediated through the increased expression of IL-9 and IL-13. We lastly show in both chronic and memory recall models of AAD that blockade of TL1A signaling decreases the multicytokine Th9 cell population and attenuates the allergic phenotype. Taken together, these data demonstrate that TL1A promotes development of multi-cytokine Th9 cells that drive allergic airway diseases and that targeting TL1A could be an effective approach for modifying disease.