Transcription Factor KLF2 in Dendritic Cells Downregulates Th2 Programming via the HIF-1α/Jagged2/Notch Axis

Abstract

ABSTRACT The adaptive immune response is tightly regulated by complex signals in dendritic cells (DCs). Although Th2 polarization is dictated by defined functional DC subsets, the molecular factors that govern the amplitude of these responses are not well understood. Krüppel-like factor 2 (KLF2) is a transcription factor that negatively regulates the activation of numerous immune cells in response to stimuli. Here, we demonstrate that suppression of KLF2 in conditioned DCs preferentially amplifies Th2 responses in two model systems, one of which is a prototypical intracellular pathogen and the other an allergen. This elevation in Th2 responses was dependent on contact-mediated Notch signaling in vitro and in vivo. A deficiency of KLF2 increased the expression of Notch ligand Jagged2 via hypoxia-inducible factor 1α (HIF-1α), which led to Th2 amplification. Our results revealed a novel circuit in DCs for Th2 polarization that is governed by KLF2. IMPORTANCE Dendritic cells are the key element that bridges innate and adaptive immunity. A complex and not-well-understood area in dendritic cell biology is the regulatory network that predetermines or moderates their function to shape the adaptive immune response. Our study for the first time demonstrates that KLF2, a transcription factor, conditions dendritic cells to regulate Th2 responses via a Jagged2/Notch axis. Downregulation of KLF2 expression in dendritic cells may provide a beneficial effect for treatment of diseases such as obesity or parasitic infections but may be deleterious in the case of invasion by intracellular pathogens. Strategies to tune KLF2 may be useful for future therapeutic approaches to particular diseases of mankind.