The Role of the Immune System and in Immune-Derived Signaling Molecules in Recovery from CNS Injury.

A body of experimental evidence suggests that T cells mediate neuroprotection following central nervous system (CNS) injury, although their antigen specificity and the precise mechanism underlying their beneficial effect are unknown. Here we provide compelling evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). This antigen-independent response leads to MyD88-dependent Th2 induction by the damage associated molecular mediator IL-1β, which is derived from microglia in the injured CNS tissue. T cell-derived IL-4 then directly protects and induces recovery of injured neurons via neuronal IL-4 receptors through potentiation of neurotrophin signaling. These findings shed a new light on the immune response to CNS injury and provide the first demonstration of a protective T-cell response induced by the molecular signature of the injured tissue independent of MHCII-TCR interactions. Our results point to IL-4 as a key immune molecule mediating neuroprotection and recovery of the injured CNS. These findings further illuminate the mechanisms for neuroprotection after CNS trauma, and have implications for the development of safe immune-based therapies for CNS injuries and neurodegenerative disorders.