title: MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4.
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.forename: James T
authors.initials: JT
authors.lastname: Walsh
authors.forename: Sven
authors.initials: S
authors.lastname: Hendrix
authors.forename: Francesco
authors.initials: F
authors.lastname: Boato
authors.forename: Igor
authors.initials: I
authors.lastname: Smirnov
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zheng
authors.forename: John R
authors.initials: JR
authors.lastname: Lukens
authors.forename: Sachin
authors.initials: S
authors.lastname: Gadani
authors.forename: Daniel
authors.initials: D
authors.lastname: Hechler
authors.forename: Greta
authors.initials: G
authors.lastname: Gölz
authors.forename: Karen
authors.initials: K
authors.lastname: Rosenberger
authors.forename: Thomas
authors.initials: T
authors.lastname: Kammertöns
authors.forename: Johannes
authors.initials: J
authors.lastname: Vogt
authors.forename: Christina
authors.initials: C
authors.lastname: Vogelaar
authors.forename: Volker
authors.initials: V
authors.lastname: Siffrin
authors.forename: Ali
authors.initials: A
authors.lastname: Radjavi
authors.forename: Anthony
authors.initials: A
authors.lastname: Fernandez-Castaneda
authors.forename: Alban
authors.initials: A
authors.lastname: Gaultier
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
mesh_terms: D000818:Animals; D001369:Axons / Q000276:immunology* / Q000473:pathology; D001930:Brain Injuries / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases