TL1A promotes a multi-cytokine Th9 cell phenotype

Abstract

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 signaling has been shown to increase IL-9 production by 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 Th9 cell cultures through flow cytometric analyses. We also show that the Il9 and Il13 promoter and enhancer regions are differentially accessible in response to TL1A over a five-day culture period through chromatin accessibility assays. At the Il9 locus, TL1A enhances binding of IRF4, BATF, and PPARg. Mechanistically, this is linked to decreased H3K9 tri-methylation and increased H3K4 tri-methylation at Il9 enhancer region CNS2. At the Il13 locus, TL1A enhances binding of BATF at the Il13 promoter alongside decreased H3K9 tri-methylation and increased H3K4 tri-methylation. Ongoing experiments define the function of TL1A-induced multi-cytokine producing cells. Together, these data indicate that TL1A contributes to heterogeneity of IL-9-secreting T cell populations. Supported by NIH Combined Adult and Pediatrics Pulmonary Research Training Program T32