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

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Item Type:Article
Title:MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4
Creators Name:Walsh, J.T. and Hendrix, S. and Boato, F. and Smirnov, I. and Zheng, J. and Lukens, J.R. and Gadani, S. and Hechler, D. and Goelz, G. and Rosenberger, K. and Kammertoens, T. and Vogt, J. and Vogelaar, C. and Siffrin, V. and Radjavi, A. and Fernandez-Castaneda, A. and Gaultier, A. and Gold, R. and Kanneganti, T.D. and Nitsch, R. and Zipp, F. and Kipnis, J.
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.
Keywords:Axons, Brain Injuries, CD4-Positive T-Lymphocytes, Extracellular Signal-Regulated MAP Kinases, Histocompatibility Antigens Class II, Interleukin-4, Knockout Mice, MAP Kinase Signaling System, Myeloid Differentiation Factor 88, Neurodegenerative Diseases, Proto-Oncogene Proteins c-akt, T-Cell Antigen Receptors, Animals, Mice
Source:Journal of Clinical Investigation
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Volume:125
Number:2
Page Range:699-714
Date:2 February 2015
Additional Information:Erratum in: J Clin Invest 2015 May 4 [epub ahead of print]
Official Publication:https://doi.org/10.1172/JCI76210
PubMed:View item in PubMed

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