Myelin oligodendrocyte glycoprotein reactive Th17 cells drive Janus Kinase 1 dependent transcriptional reprogramming in astrocytes and alter cell surface cytokine receptor profiles during experimental autoimmune encephalomyelitis.
Multiple sclerosis (MS) is an autoimmune demyelinating disease affecting the central nervous system (CNS). T helper (Th) 17 cells are involved in the pathogenesis of MS and its animal model of experimental autoimmune encephalomyelitis (EAE) by infiltrating the CNS and producing effector molecules that engage resident glial cells. Among these glial cells, astrocytes have a central role in coordinating inflammatory processes by responding to cytokines and chemokines released by Th17 cells. In this study, we examined the impact of pathogenic Th17 cells on astrocytes in vitro and in vivo. We identified that Th17 cells reprogram astrocytes by driving transcriptomic changes partly through a Janus Kinase (JAK)1-dependent mechanism, which included increased chemokines, interferon-inducible genes, and cytokine receptors. In vivo, we observed a region-specific heterogeneity in the expression of cell surface cytokine receptors on astrocytes, including those for TGFß, IL-10, IL-1, IL-17, IFN-?, and TNF-a. Additionally, these receptors were dynamically regulated during EAE induced by adoptive transfer of myelin-reactive Th17 cells. This study overall provides evidence of Th17 cell reprogramming of astrocytes, which may drive changes in the astrocytic responsiveness to cytokines during autoimmune neuroinflammation. Overall design: To test if Th17 cells were activating JAK1-dependent signaling in astrocytes, we knocked down JAK1 in the astrocytes and cultured the astrocytes with and without pathogenic Th17 cells. Following co-culture with Th17 cells, T cells were removed, and astrocyte RNA isolated for analysis. The experimental groups are 1) Astrocytes non-targeting siRNA, no Th17 cells; 2) Astrocytes non-targeting siRNA with Th17 cells; 3) Astrocytes JAK1 siRNA, no Th17 cells; 4) Astrocytes JAK1 siRNA with Th17 cells. Three biological replicates of astrocytes were analyzed for each condition.