The role of T helper 9 cells and interleukin-9 in allergic diseases

Allergic diseases, including asthma and food allergies, pose a global public health challenge. However, the complex immunopathological mechanisms have not been fully elucidated yet. Although T helper 2 (Th2) cells are regarded as central drivers, they cannot fully explain the clinical heterogeneity and therapeutic resistance of these diseases. This review aimed to systematically illustrate the key roles and regulatory mechanisms of T helper 9 (Th9) cells and their effector cytokine interleukin-9 (IL-9) in various allergic diseases. Th9 cells differentiate under the synergistic induction of transforming growth factor-β (TGF-β) and interleukin-4 (IL-4), and their specific transcription factors (such as Spi-1 proto-oncogene (PU.1), Interferon Regulatory Factor 4 (IRF4)) and epigenetic modifications jointly regulate IL-9 expression. IL-9 acts on mast cells, B cells, eosinophils, and epithelial cells, forming a positive-feedback inflammatory amplification loop that connects adaptive immunity to structural tissue cells. Although drug development targeting IL-9 (such as enokizumab) has faced challenges, intervention strategies targeting key nodes of this axis remain a highly promising research direction. The Th9/IL-9 axis, as a critical hub linking immune activation and pathological tissue changes, provides a new theoretical framework for understanding the heterogeneity of allergic diseases and represents a potential therapeutic target.