Human "TH9" cells are a subpopulation of PPAR-γ+ TH2 cells

Abstract

Although T_H1, T_H2, and T_H17 cells are well-defined T_H cell lineages in humans, it remains debated whether IL-9-producing T_H cells represent a bona fide "T_H9" lineage. Our understanding of the cellular characteristics and functions of IL-9-producing T_H cells in humans is still nascent. Here, we report that human IL-9-producing T_H cells express the chemokine receptors CCR4 and CCR8, produce high levels of IL-5 and IL-13, and express T_H2 lineage-associated transcription factors. In these cells, IL-9 production is activation dependent, transient, and accompanied by down-regulation of T_H2 cytokines, leading to an apparent "T_H9" phenotype. IL-9⁺ T_H2 cells can be distinguished from "conventional" T_H2 cells based on their expression of the transcription factor PPAR-γ. Accordingly, PPAR-γ is induced in naïve T_H cells by priming with IL-4 and TGF-β ("T_H9" priming) and is required for IL-9 production. In line with their identity as early activated T_H2 cells, IL-9⁺ T_H2 cells are found in acute allergic skin inflammation in humans. We propose that IL-9-producing T_H cells are a phenotypically and functionally distinct subpopulation of T_H2 cells that depend on PPAR-γ for full effector functions.