Th9 cells and IL-9 in autoimmune disorders: Pathogenesis and therapeutic potentials

Abstract

Naïve CD4⁺ T cells are pleiotropically divided into various T helper (Th) cell subsets, according to their pivotal roles in the regulation of immune responses. The differentiation of Th9 cells, an interleukin (IL)-9 producing subset, can be impacted by specific environmental cues, co-stimulation with transforming growth factor β (TGF-β) and IL-4, and other regulatory factors. Although IL-9 has been recognized as a classical Th2-related cytokine, recent studies have indicated that IL-9-producing cells contribute to a group of autoimmune disorders including systemic lupus erythematosus (SLE), multiple sclerosis (MS), inflammatory bowel diseases (IBD), rheumatoid arthritis (RA) and psoriasis. Studies of Th9 cells in autoimmune diseases, although in their infancy, are expected to be of growing interest in the study of potential mechanisms of cytokine regulatory pathways and autoimmune pathogenesis. Several in vitro and in vivo pre-clinical trials have been conducted to explore potential therapeutic strategies by targeting the IL-9 pathway. Specifically, anti-IL-9 monoclonal antibodies (mAbs) and IL-9 inhibitors may potentially be used for the clinical treatment of allergic diseases, autoimmune diseases or cancers. Here, we review recent research on Th9 cells and IL-9 pertaining to cell differentiation, biological characteristics and pivotal cellular inter-relationships implicated in the development of various diseases.

Introduction

CD4⁺ T helper (Th) cells functionally differentiate into various subsets, which are involved in the development of allergic, inflammatory and autoimmune diseases. In the past 20 years, Th1 cells and Th2 cells, characterized by different cytokine secretion patterns, have been regarded as the two main quintessential archetypes differentiated from naive CD4⁺ T cells. Th1 cells mainly produce IL-2, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), whereas Th2 cells predominately secrete IL-4, IL-5, IL-6 and IL-13. In recent years, several other distinct subsets of Th cells have been identified, including Th17, Th22 and regulatory T cells (Tregs). These distinct subsets can be distinguished by the specific cytokines and transcription factors, which each expresses, and their products define the functional roles of different Th cell subsets in diseases (Table 1).

In a broad sense, various CD4⁺ T cell subsets such as Th1, Th2, Th17, Th22 and Treg cells have been implicated in the pathogenesis of systemic lupus erythematosus (SLE) [1], multiple sclerosis (MS) [2], inflammatory bowel diseases (IBD) [3], and rheumatoid arthritis (RA) [4]. More recently, a new effector T-cell subset that secretes the cytokine IL-9 has been identified as Th9 cells. The expression of IL-9 in this effector T cell subset occurs in the presence of both IL-4 and TGF-β, whereas IL-4 alone has a minimal effect on IL-9 expression during naive T-cell polarization [5]. Research over the last decade has suggested that Th9 cells possess a myriad of opposing pro-inflammatory and anti-inflammatory functions in autoimmune diseases.

Autoimmune diseases are a series of disorders characterized by immune system dysregulations, leading to inflammatory damage in genetically and environmentally susceptible individuals. Although the exact mechanism underlying autoimmune diseases remains elusive, recent studies have revealed a functional role of Th9 cells and IL-9 in their pathogenesis, especially in experimental autoimmune encephalitis (EAE), a classical experimental model for MS [2], [6], [7], [8]. The lack of any significant efficacy in the conventional treatment of autoimmune diseases based on previously known cytokines produced by subsets such as Th1 and Th2 cells may suggest the existence of other factors attributable to the pathogenesis of these diseases. This unmet need to identify these factors has led to a great deal of research in defining IL-9-mediated clinical syndromes. Current studies of IL-9 and the Th9-cell subset have provided new insights in understanding the pathogenesis and therapeutic potentials of various autoimmune diseases.