Inhibition of the TNF Family Cytokine RANKL Prevents Autoimmune Inflammation in the Central Nervous System

•T cell-specific Tnfsf11 knockout mice are resistant to EAE•RANKL-deficient T cells fail to efficiently infiltrate into the CNS•T cells induce production of CCL20 by astrocytes through RANKL•Pharmacological inhibition of RANKL prevents EAE

SummaryThe central nervous system (CNS) is an immunologically privileged site protected from uncontrolled access of T cells by the blood-brain barrier (BBB), which is breached upon autoimmune inflammation. Here we have shown that receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) on T cells regulates C-C type chemokine ligand 20 (CCL20) production by astrocytes and T cell localization in the CNS. Importantly, mice specifically lacking RANKL in T cells were resistant to experimental autoimmune encephalomyelitis (EAE) due to altered T cell trafficking. Pharmacological inhibition of RANKL prevented the development of EAE without affecting the peripheral immune response, indicating that RANKL is a potential therapeutic target for treating autoimmune diseases in the CNS.

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