Regulatory role of T helper 9/interleukin-9: Transplantation view

Abstract

T helper 9 (Th9) cells, a subset of CD4⁺ T helper cells, have emerged as a valuable target for immune cell therapy due to their potential to induce immunomodulation and tolerance. The Th9 cells mainly produce interleukin (IL)-9 and are known for their defensive effects against helminth infections, allergic and autoimmune responses, and tumor suppression. This paper explores the mechanisms involved in the generation and differentiation of Th9 cells, including the cytokines responsible for their polarization and stabilization, the transcription factors necessary for their differentiation, as well as the role of Th9 cells in inflammatory and autoimmune diseases, allergic reactions, and cancer immunotherapies. Recent research has shown that the differentiation of Th9 cells is coregulated by the transcription factors transforming growth factor β (TGF-β), IL-4, and PU.1, which are also known to secrete IL-10 and IL-21. Multiple cell types, such as T and B cells, mast cells, and airway epithelial cells, are influenced by IL-9 due to its pleiotropic effects.

Keywords: CD4+ T cells; IL-4; IL-9; TGF-β; Th9 cells.

Fig. 1

Production of Th9 cells and their effect on immunopathology and immunity: naive CD4⁺ T cells differentiate into Th9 cells and produce pleiotropic IL-9 cytokine that can activate different cell types during inflammatory reactions.

Fig. 2

Different cytokines and transcription factors are involved in the differentiation of CD4⁺ T cells into Th9 cells.

Fig. 3

In the signaling complex of the IL-9 receptor, IL-9 operates on its heterodimeric receptor, which is composed of γ-chain and IL-9 receptor α chain.

Fig. 4

Different cell types can produce IL-9; IL-9 is a pleiotropic cytokine that has multiple effects and is produced by diverse cell types and plays important roles in inflammation and immunity.

Fig. 5

Regulation of the Il-9 gene: three elements near the Il-9 gene.

Fig. 6

The transcriptional diagram of Th9 cells indicates that the increase in T cells releasing IL-9 is influenced by the engagement of a wide range of surface receptors and cytokines. The roles of different cytokines and costimulatory molecules in the differentiation and function of Th9 cells are summarized in this figure.

Fig. 7

Role of Th9 lymphocytes in immune responses: based on the native microenvironment, Th9 lymphocytes induce autoimmunity/inflammation or tolerance.

Fig. 8

Interconnection between TGF-β and Th9 cells during transplantation: TGF-β and its signaling pathway are effective in regulating the immune system and are involved in the failure or success of transplantation.