Targeting Th9 cells in autoimmune diseases: a narrative review

Abstract

T helper 9 (Th9) cells are a newly identified subset of effector T cells, characterized by their production of IL-9, a hallmark cytokine. Transcription factors such as PU.1 and IRF4 bind to the IL9 gene promoter and transactivate its expression. IL-9 and its associated transcription factors regulate various aspects of Th9 cell biology, including proliferation, apoptosis, differentiation, and interactions with other immune cells through downstream signaling pathways. In recent years, the involvement of Th9 cells in autoimmune diseases has been widely investigated. Multiple studies have reported the aberrant expression of IL-9, PU.1, and IRF4 in these inflammatory conditions, and functional analyses have demonstrated their significant roles in disease development. In this review, we comprehensively summarize the relationship among Th9-related cytokines, transcription factors, and 14 autoimmune diseases based on both in vivo and in vitro evidence. We further discuss the regulatory effects of intracellular and extracellular signaling pathways on Th9 cell functions. This compilation of findings may facilitate future research and the development of clinical strategies targeting Th9 cells in autoimmune diseases.

Keywords: IL-9; Th9 cells; autoimmunity; inflammation; therapeutic target.

Figure 1

Th9-related signaling. Th9 cell differentiation and function of cytokines, transcription factors such as IL-9 and PU.1 were differently regulated by extracellular signaling, transmembrane proteins, intracellular transcription factors, metabolic components, and pathogen—for instance, inflammatory cytokines IL-1β, TGF-β, IL-4, and IL-2 activate STAT5, which then inhibit BCL-6 activation, leading to the reduced expression of IL-9. ITK interacts with IL-2 and then promotes STAT5 activation, resulting in the downregulated expression of BCL-6 and less IL-9 generation. TL1A activates the STAT6-NF-κB-BATF3 axis and then promotes Th9 differentiation. IFN-γ induces DC generation of IL-27, which then activates STAT1, but inactivates STAT3, leading to Th9 cell proliferation and migration.

Figure 2

Association of Th9 cells, related cytokines, and transcription factors in rheumatoid arthritis. CD4⁺ T cells, RF-FLS, macrophages, neutrophils, and Th17 cells from RA patients were stimulated with IL-9, showing increased inflammation of the cells. On the contrary, inhibition of PU.1 in the cells abrogated IL-9-mediated effects. Coculturing PU.1^-/- Th9 cells with RA-FLS inhibited the proliferation and migration of RA-FLS and downregulated the production of inflammatory matrix metalloproteinases. RA-FLS, rheumatoid arthritis fibroblast-like synoviocytes.