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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/18682

Title: MHCII-independent CD4(+) T cells protect injured CNS neurons via IL-4
Authors: Walsh, James T.
HENDRIX, Sven
Boato, Francesco
Smirnov, Igor
Zheng, Jingjing
Lukens, John R.
Gadani, Sachin
Hechler, Daniel
Goelz, Greta
Rosenberger, Karen
Kammertoens, Thomas
Vogt, Johannes
Vogelaar, Christina
Siffrin, Volker
Radjavl, Ali
Fernandez-Castaneda, Anthony
Gaultier, Alban
Gold, Ralf
Kanneganti, Thirumala-Devi
Nitsch, Robert
Zipp, Frauke
Kipnis, Jonathan
Issue Date: 2015
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Citation: JOURNAL OF CLINICAL INVESTIGATION, 125 (2), p. 699-714
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.
Notes: Address correspondence to: Frauke Zipp, Neurology Department, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany. Phone: 0049.6131.17.2510; E-mail: Frauke.zipp@unimedizin-mainz.de. Or to: Jonathan Kipnis, Department of Neuroscience, University of Virginia, 409 Lane Rd., MR4, Charlottesville, Virginia 22908, USA. Phone: 434.982.3858; E-mail: kipnis@virginia.edu.
URI: http://hdl.handle.net/1942/18682
Link to publication: http://www.jci.org/articles/view/76210#sd
DOI: 10.1172/JCI176210
ISI #: 000348962700026
ISSN: 0021-9738
Category: A1
Type: Journal Contribution
Validation: ecoom, 2016
Appears in Collections: Research publications

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