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

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Abstract

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⁺ 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⁺ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration.

Authors

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