Th17 cell LFA-1 engagement-mediated IL-17A and GM-CSF mRNA stabilization is HuR-dependent (54.14)

Abstract

Abstract Recent studies demonstrate that the β2 integrin LFA-1 is required for entry of encephalitogenic Th17 cells into the brain parenchyma during murine experimental autoimmune encephalomyelitis (EAE). We previously showed that LFA-1 engagement by its ligand, intracellular adhesion molecule-1 (ICAM-1), in human T cells results in translocation of the RNA-binding protein HuR and stabilization of TNFα and IFNγ mRNAs. The role of HuR in the regulation of Th17 cell-mediated inflammation is unknown. We hypothesize that LFA-1 engagement in Th17 cells leads to increased neuropathology-relevant cytokine expression at inflammatory sites through HuR-mediated mRNA stabilization. LFA-1 engagement led to HuR nuclear-to-cytoplasmic translocation and stabilization of both IL-17A and GM-CSF transcripts in mouse EL4 T cells, in vitro differentiated mouse Th17 cells and human primary T cells. EL4 and human primary T cell adhesion to ICAM-1 led to increased levels of IL-17A and GM-CSF mRNA in HuR immunoprecipitates. LFA-1 engagement-stimulated IL-17A and GM-CSF mRNA stabilization was lost in HuR-deficient Th17 cells generated from RORcγt-Cre/HuRflox/flox mice. We conclude that LFA-1 engagement induces HuR-dependent stabilization of the otherwise labile GM-CSF and IL-17A transcripts in Th17 cells, and that this may be highly relevant in Th17 cell-induced CNS pathology. Future experiments will focus on the role of Th17 cell HuR in the EAE model.