Journal Article

MHCII-independent CD4^sup +^ T cells protect injured CNS neurons via IL-4

Hechler, Daniel, Vogt, Johannes, Kanneganti, Thirumala-Devi, Smirnov, Igor, Radjavi, Ali, Rosenberger, Karen, Nitsch, Robert, Kammertöns, Thomas, Gadani, Sachin, Gold, Ralf, Hendrix, Sven, Zipp, Frauke, Gaultier, Alban, Gölz, Greta, Kipnis, Jonathan, Vogelaar, Christina, Lukens, John R, Zheng, Jingjing, Walsh, James T, Boato, Francesco, Siffrin, Volker, Fernandez-Castaneda, Anthony

2015

Overview

A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4^sup +^ T cells from wild-type mice, but not from IL-4-deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell-derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4-producing CD4^sup +^ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration.

• Publisher: American Society for Clinical Investigation
• Subject: Antigens / Biomedical research / Colleges & universities / Laboratory animals / Lymphocytes / Neurodegeneration / Neurons / Optic nerve / Rodents / Spinal cord injuries / Statistical methods / T cell receptors