The symphony of the ninth: the development and function of Th9 cells

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CD4+ T helper cells are obligate regulators of inflammatory disease. An expanding cadre of T helper (Th) subsets, specialized for promoting particular types of inflammation, function through the secretion of a restricted set of cytokines. The latest addition to the list of subsets is the Th9 cell that secretes IL-9 as a signature cytokine and contributes to several classes of inflammatory disease. In this review we focus on recent advances in understanding the development of Th9 cells, and how Th9 cells contribute to the orchestration of disease.

Highlights

Th9 cells are a T helper cell subset that secretes IL-9 as a signature cytokine. ► Th9 cell development requires transcription factors including PU.1, IRF4 and STAT6. ► Th9 cells promote inflammation in autoimmunity and allergic disease.

Introduction

Naïve CD4+ T helper (Th) cells, after encountering specific antigen, become activated and differentiate into effector T helper subsets, each characterized by a distinct pattern of cytokine secretion and function. Th1 cells mediate immunity to intracellular pathogens, Th2 cells provide protection against extracellular parasites, and Th17 cells are involved in resistance to extracellular bacteria and fungal infections. Another effector subset, termed Th9, secretes IL-9 and may be involved in immune-mediated diseases ranging from autoimmunity to asthma. The biology of IL-9 has been recently reviewed [1, 2, 3]; this review is focused on discussing recent advances in our understanding of the development of IL-9-secreting T cells, and the functions of Th9 cells in vivo.

Section snippets

The pathway towards Th9 differentiation

T helper cells secreting IL-9 are primed in response to TGF-β and IL-4 and are termed Th9 [4, 5]. Both signals are required as cells that lack IL-4 or TGF-β signaling components fail to develop into IL-9-secreting cells [4, 5, 6]. Since Th9 cells require balanced signals from TGF-β and IL-4 [4, 5, 6], each cytokine likely leads to the induction of transcription factors that regulate IL-9 production, and the expression of other genes associated with the Th9 phenotype. The TGF-β signal, which

Functions of Th9 cells

Th9 cells are pro-inflammatory, but appear to function in a broad spectrum of autoimmune diseases and allergic inflammation. Their precise function likely depends upon the tissue microenvironment and other T helper cell cytokines that are present in the inflammatory milieu.

Th9 cells contribute to inflammation in several autoimmune disease models. Th9 cells induce inflammation in a T cell transfer colitis model [5]. Mice that received Th9 cells only, lost weight and developed a moderate colitis.

Concluding remarks

The Th9 subset develops in response to combined signals from TGF-β and IL-4 among a cacophony of other cytokines in the extracellular milieu. The transcriptional network that regulates Th9 development includes TGF-β-induced Sfpi1, and IL-4-induced STAT6 that induces IRF4 as it represses Foxp3 and T-bet (Figure 1). Additional transcription factors, possibly downstream of these and additional cytokines, undoubtedly harmonize in efficient transcription of the Il9 gene.

IL-9 promotes inflammation by

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank the Kaplan lab members for helpful input. Preparation of this article was supported by Public Health Service grant AI057459 and the Wells Center for Pediatric Research.

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