Interleukin-1b-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 (TH-GM-CSF) are a distinct T helper cell subset is lacking. Herein we demonstrate that interleukin (IL)-1b exclusively drives differentiation of naive CD4+ T cells into TH-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 (RORt) required for TH17 differentiation. In vivo, TH-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 TH-GM-CSF cell phenotype is stable and distinct from the TH17 genetic program, but IL-1b can convert pre-formed TH17 cells into TH-GM-CSF cells, thereby accounting for previously reported associations between IL-17 and GM-CSF. Together, our results newly identify IL-1b/NFκB-dependent TH-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. Funding Statement: Huabao Xiong was supported by NIH funding RO1AI104688. Peter. S Heeger was supported by RO1AI132405 and RO1AI071185. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The animal study protocols were approved by the Institutional Animal Care and Use Committees of Mount Sinai School of Medicine.