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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., Hendrix, S., Boato, F., Smirnov, I., Zheng, J., Lukens, J.R., Gadani, S., Hechler, D., Gölz, G., Rosenberger, K., Kammertöns, T., Vogt, J., Vogelaar, C., Siffrin, V., Radjavi, A., Fernandez-Castaneda, A., Gaultier, A., Gold, R., Kanneganti, T.D., Nitsch, R., 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 |
| Volume: | 125 |
| Number: | 2 |
| Page Range: | 699-714 |
| Date: | 2 February 2015 |
| Additional Information: | Copyright © 2015, American Society for Clinical Investigation | Erratum in: J Clin Invest. 2015;125(6):2547. doi:10.1172/JCI82458. |
| Official Publication: | https://doi.org/10.1172/JCI76210 |
| PubMed: | View item in PubMed |
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