The 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.
The specific function of RANKL expressed by T cells in the context of immune responses remains enigmatic. Takayanagi and colleagues show that RANKL on T cells regulates CCL20 expression by astrocytes and the recruitment of T cells into the central nervous system (CNS), a critical step in CNS autoimmunity.