The study investigates the role of T-helper type 17 (T<Hsub>17</Hsub>) lymphocytes in the disruption of the blood-brain barrier (BBB) and central nervous system (CNS) inflammation, particularly in multiple sclerosis. Key findings include: 1. **T<Hsub>17</Hsub> Lymphocytes and BBB Disruption:** - T<Hsub>17</Hsub> lymphocytes express IL-17 and IL-22 receptors on BBB endothelial cells (BBB-ECs). - IL-17 and IL-22 disrupt BBB tight junctions both in vitro and in vivo. - T<Hsub>17</Hsub> lymphocytes efficiently transmigrate across BBB-ECs and highly express granzyme B, which kills human neurons and promotes CNS inflammation by recruiting CD4+ lymphocytes. 2. **In Vitro and In Vivo Models:** - In vitro, T<Hsub>17</Hsub> lymphocytes migrated more avidly across the BBB compared to T<Hsub>1</Hsub> or ex vivo CD4+ lymphocytes. - In vivo, MOG-specific T<Hsub>1</Hsub> and T<Hsub>17</Hsub> lymphocytes were transferred to Rag1−/− mice, and both types of lymphocytes accessed the CNS equally well. - In multiple sclerosis lesions, CD45RO+ cells positive for IL-17 or IL-22 were detected, confirming their infiltration into the CNS. 3. **Cytolytic Activity of T<Hsub>17</Hsub> Lymphocytes:** - T<Hsub>17</Hsub> lymphocytes express granzyme B, which confers significant cytolytic activity against human fetal neuron-enriched cultures. 4. **BBB Integrity and Receptor Expression:** - IL-17R and IL-22R are expressed on a subset of human BBB-ECs and are strongly upregulated in heavily infiltrated multiple sclerosis lesions. - IL-17 and IL-22 treatment of BBB-ECs increases permeability and disrupts tight junction proteins like occludin and ZO-1. 5. **Lymphocyte Migration and Cytokine Secretion:** - IL-17 and IL-22 promote the transmigration of CD4+ lymphocytes across BBB-ECs, likely through enhanced secretion of CCL2 (MCP-1). These findings highlight the critical role of T<Hsub>17</Hsub> lymphocytes in the pathogenesis of multiple sclerosis by disrupting the BBB and promoting CNS inflammation.The study investigates the role of T-helper type 17 (T<Hsub>17</Hsub>) lymphocytes in the disruption of the blood-brain barrier (BBB) and central nervous system (CNS) inflammation, particularly in multiple sclerosis. Key findings include: 1. **T<Hsub>17</Hsub> Lymphocytes and BBB Disruption:** - T<Hsub>17</Hsub> lymphocytes express IL-17 and IL-22 receptors on BBB endothelial cells (BBB-ECs). - IL-17 and IL-22 disrupt BBB tight junctions both in vitro and in vivo. - T<Hsub>17</Hsub> lymphocytes efficiently transmigrate across BBB-ECs and highly express granzyme B, which kills human neurons and promotes CNS inflammation by recruiting CD4+ lymphocytes. 2. **In Vitro and In Vivo Models:** - In vitro, T<Hsub>17</Hsub> lymphocytes migrated more avidly across the BBB compared to T<Hsub>1</Hsub> or ex vivo CD4+ lymphocytes. - In vivo, MOG-specific T<Hsub>1</Hsub> and T<Hsub>17</Hsub> lymphocytes were transferred to Rag1−/− mice, and both types of lymphocytes accessed the CNS equally well. - In multiple sclerosis lesions, CD45RO+ cells positive for IL-17 or IL-22 were detected, confirming their infiltration into the CNS. 3. **Cytolytic Activity of T<Hsub>17</Hsub> Lymphocytes:** - T<Hsub>17</Hsub> lymphocytes express granzyme B, which confers significant cytolytic activity against human fetal neuron-enriched cultures. 4. **BBB Integrity and Receptor Expression:** - IL-17R and IL-22R are expressed on a subset of human BBB-ECs and are strongly upregulated in heavily infiltrated multiple sclerosis lesions. - IL-17 and IL-22 treatment of BBB-ECs increases permeability and disrupts tight junction proteins like occludin and ZO-1. 5. **Lymphocyte Migration and Cytokine Secretion:** - IL-17 and IL-22 promote the transmigration of CD4+ lymphocytes across BBB-ECs, likely through enhanced secretion of CCL2 (MCP-1). These findings highlight the critical role of T<Hsub>17</Hsub> lymphocytes in the pathogenesis of multiple sclerosis by disrupting the BBB and promoting CNS inflammation.