TGF‐β interactions with IL‐1 family members trigger IL‐4‐independent IL‐9 production by mouse CD4⁺ T cells

Abstract

TGF-b and IL-4 were recently shown to selectively upregulate IL-9 production by naïve CD4 1 T cells. We report here that TGF-b interactions with IL-1a, IL-1b, IL-18, and IL-33 have equivalent IL-9-stimulating activities that function even in IL-4-deficient animals. This was observed after in vitro antigenic stimulation of immunized or unprimed mice and after polyclonal T-cell activation. Based on intracellular IL-9 staining, all IL-9-producing cells were CD4 1 and 80-90% had proliferated, as indicated by reduced CFSE staining. In contrast to IL-9, IL-13 and IL-17 were strongly stimulated by IL-1 and either inhibited (IL-13) or were unaffected (IL-17) by addition of TGF-b. IL-9 and IL-17 production also differed in their dependence on IL-2 and regulation by IL-1/IL-23. As IL-9 levels were much lower in Th2 and Th17 cultures, our results identify TGF-b/IL-1 and TGF-b/IL-4 as the main control points of IL-9 synthesis.

IL-9 Promotes Th17 Cell Migration into the Central Nervous System via CC Chemokine Ligand-20 Produced by Astrocytes

“…1) or when anti-IL-4 Abs are added (data not shown), indicating that IL-9 production by naive CD4 + T cells stimulated with TGF-b plus IL-25 or IL-1b is also IL-4-dependent. However, others have claimed that IL-9 production under these conditions is IL-4-independent (12,16). Although the reason for this discrepancy requires further studies, IL-25 was originally associated with Th2 differentiation via IL-4 production and STAT6-mediated signal transduction (32,33).…”

“…IL-9-producing helper T cells (Th9) were recently discovered and have been reported to be induced by the stimulating naive CD4 + T cells with TGF-b plus IL-4, IL-6, IL-25, or IL-1 family cytokines, including IL-1a, IL-1b, IL-18, and IL-33, and even with TGF-b alone (12)(13)(14)(15)(16)(17). However, other reports have suggested that both Th2 and Th17 cells produce IL-9 (14,15).…”

Interleukin-33 and the function of innate lymphoid cells

“…Similar to other IL-1 cytokines, IL-33 can induce cytokine production in effector Th2 cells independent of T cell receptor (TCR) triggering; a process enhanced by the presence of a signal transducer and activator of transcription (STAT) 5 activating cytokine [41]. More recently, IL-33 in combination with transforming growth factor (TGF)-b, has been shown to enhance IL-9 production from CD4 T cells [42,43]. IL-33 also regulates the activity of cytotoxic CD8 T cells.…”

Interleukin-25 (IL-25) Promotes Efficient Protective Immunity against Trichinella spiralis Infection by Enhancing the Antigen-Specific IL-9 Response

“…IL-9 production can be regulated by several cytokines (16)(17)(18)(19)(20); however, the regulation of Th9 cell differentiation during helminth infection is less clear. In vitro, TGF-␤ and IL-4 were the major stimulators of Th9 cell induction (16,17).…”