Interleukin-1β-induced IRAK1 ubiquitination is required for TH-GM-CSF cell differentiation in T cell-mediated inflammation

Abstract

Accumulating evidence suggests granulocyte macrophage-colony stimulating factor (GM-CSF) can function as an inflammatory mediator, but whether GM-CSF-producing CD4⁺ T cells (T_H-GM-CSF) are a distinct T helper cell subset is lacking. Herein we demonstrate that interleukin (IL)-1β exclusively drives differentiation of naïve CD4⁺ T cells into T_H-GM-CSF cells via inducing ubiquitination of IL-1 receptor-associated kinase 1 (IRAK1) and subsequent activation of the transcription factor NF-kappaB (NF-κB), independent of RAR-related orphan receptor gamma (RORγt) required for T_H17 differentiation. In vivo, T_H-GM-CSF cells are present in murine Citrobacter Rodentium infections and mediate colitis following adoptive transfer of CD4⁺ T cells into Rag1^-/- mice via GM-CSF-induced macrophage activation. The T_H-GM-CSF cell phenotype is stable and distinct from the T_H17 genetic program, but IL-1β can convert pre-formed T_H17 cells into T_H-GM-CSF cells, thereby accounting for previously reported associations between IL-17 and GM-CSF. Together, our results newly identify IL-1β/NF-κB-dependent T_H-GM-CSF cells as a unique T helper cell subset and highlight the importance of CD4⁺ T cell-derived GM-CSF induced macrophage activation as a previously undescribed T cell effector mechanism.