T helper 17 (Th17) lymphocytes promote blood-brain barrier (BBB) disruption and central nervous system (CNS) inflammation in multiple sclerosis (MS). The study shows that Th17 cells express IL-17 and IL-22 receptors on BBB endothelial cells, and that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Th17 cells efficiently transmigrate across BBB-ECs, highly express granzyme B, and kill human neurons, promoting CNS inflammation through CD4+ lymphocyte recruitment. Th17 cells are more efficient than Th1 cells in crossing the BBB. In vitro and in vivo experiments confirm that Th17 cells can cross the BBB and contribute to MS lesion formation. Th17 cells also express cytolytic molecules like granzyme B, which enables them to kill human neurons. IL-17 and IL-22 receptors are expressed on human BBB-ECs, and their activation increases BBB permeability. IL-17 and IL-22 induce the expression of CCL2, promoting lymphocyte migration across the BBB. These findings highlight the role of Th17 cells in BBB disruption and CNS inflammation in MS and experimental autoimmune encephalomyelitis (EAE). The study also shows that Th17 cells coexpress IL-17, IL-22, and granzyme B, contributing to their high encephalitogenic potential.T helper 17 (Th17) lymphocytes promote blood-brain barrier (BBB) disruption and central nervous system (CNS) inflammation in multiple sclerosis (MS). The study shows that Th17 cells express IL-17 and IL-22 receptors on BBB endothelial cells, and that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Th17 cells efficiently transmigrate across BBB-ECs, highly express granzyme B, and kill human neurons, promoting CNS inflammation through CD4+ lymphocyte recruitment. Th17 cells are more efficient than Th1 cells in crossing the BBB. In vitro and in vivo experiments confirm that Th17 cells can cross the BBB and contribute to MS lesion formation. Th17 cells also express cytolytic molecules like granzyme B, which enables them to kill human neurons. IL-17 and IL-22 receptors are expressed on human BBB-ECs, and their activation increases BBB permeability. IL-17 and IL-22 induce the expression of CCL2, promoting lymphocyte migration across the BBB. These findings highlight the role of Th17 cells in BBB disruption and CNS inflammation in MS and experimental autoimmune encephalomyelitis (EAE). The study also shows that Th17 cells coexpress IL-17, IL-22, and granzyme B, contributing to their high encephalitogenic potential.