Identifying novel regulators of T cell CNS infiltration in Experimental Autoimmune Encephalitis

Abstract

Abstract T helper 17 (Th17) lymphocytes promote immunity in many contexts, including infection clearance, mucosal barrier homeostasis, and autoimmunity. IL-17A producing Th17 cells differentiate from naïve precursors upon antigen encounter with specific cytokines. One important mediator of Th17 cell differentiation downstream of cytokine signaling, is the AP-1 family transcription factor, JunB. JunB is a master regulator of Th17 cell fate, both promoting expression of Th17 lineage-specific genes and suppressing those of alternative effector fates. Studies in mice with JunB deficient CD4 T cells reveal that JunB is a key arbiter of pathogenesis in the experimental autoimmune encephalitis (EAE) model of autoimmunity. In addition to displaying an increased proportion of alternative T helper cell fates, JunB CD4 T cell knockout (KO) mice are completely rescued from EAE symptoms. CD4 T cells fail to infiltrate the central nervous system (CNS) in these animals, despite retaining a significant population of IL-17A producing cells in other niches. Thus, JunB-deficient mice represent a compelling model for investigating the molecular determinants of encephalitogenic T cell infiltration into the CNS. Additionally, in vitro RNAseq experiments comparing JunB KO and WT cells differentiated under Th17 polarizing conditions, suggest several promising migration related JunB target genes which are currently under investigation. Discovery of one or more JunB targets mediating this migration defect is of great potential interest in developing targeted therapies for Th17 mediated autoimmunity.