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


  • J.T. Walsh
  • S. Hendrix
  • F. Boato
  • I. Smirnov
  • J. Zheng
  • J.R. Lukens
  • S. Gadani
  • D. Hechler
  • G. Gölz
  • K. Rosenberger
  • T. Kammertöns
  • J. Vogt
  • C. Vogelaar
  • V. Siffrin
  • A. Radjavi
  • A. Fernandez-Castaneda
  • A. Gaultier
  • R. Gold
  • T.D. Kanneganti
  • R. Nitsch
  • F. Zipp
  • J. Kipnis


  • Journal of Clinical Investigation


  • J Clin Invest 125 (2): 699-714


  • 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.