Immune-mediated neuroprotection of axotomized mouse facial motoneurons is dependent on the IL-4/STAT6 signaling pathway in CD4(+) T cells.
The CD4(+) T lymphocyte has recently been found to promote facial motoneuron (FMN) survival after nerve injury. Signal Transducer and Activator of Transcription (STAT)4 and STAT6 are key proteins involved in the CD4(+) T cell differentiation pathways leading to T helper type (Th)1 and Th2 cell development, respectively. To determine which CD4(+) T cell subset mediates FMN survival, the facial nerve axotomy paradigm was applied to STAT4-deficient (-/-) and STAT6-/- mice. A significant decrease in FMN survival 4 weeks after axotomy was observed in STAT6-/- mice compared to wild-type (WT) or STAT4-/- mice. Reconstituting STAT6-/- mice with CD4(+) T cells obtained from WT mice promoted WT levels of FMN survival after injury. Furthermore, rescue of FMN from axotomy-induced cell death in recombination activating gene (RAG)-2-/- mice (lacking T and B cells) could be achieved only by reconstitution with CD4(+) T cells expressing functional STAT6 protein. To determine if either the Th1 cytokine, interferon-gamma (IFN-gamma) or the Th2 cytokine IL-4 is involved in mediating FMN survival, facial nerve axotomy was applied to IFN-gamma-/- and IL-4-/- mice. A significant decrease in FMN survival after axotomy occurred in IL-4-/- but not in IFN-gamma-/- mice compared to WT mice, indicating that IL-4 but not IFN-gamma is important for FMN survival after nerve injury. In WT mice, intracellular IFN-gamma vs. IL-4 expression was examined in CD4(+) T cells from draining cervical lymph nodes 14 days after axotomy, and substantial increase in the production of both CD4(+) effector T cell subsets was found. Collectively, these data suggest that STAT6-mediated CD4(+) T cell differentiation into the Th2 subset is necessary for FMN survival. A hypothesis relevant to motoneuron disease progression is presented.
Deboy
Cynthia A
CA
Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago, 2160 S. 1st Avenue, Maywood, IL 60153, USA. cdeboy3@jhmi.edu
Xin
Junping
J
Byram
Susanna C
SC
Serpe
Craig J
CJ
Sanders
Virginia M
VM
Jones
Kathryn J
KJ
D000818:Animals; D019771:Axotomy; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology / Q000502:physiology; D005154:Facial Nerve / Q000276:immunology / Q000503:physiopathology* / Q000601:surgery; D020220:Facial Nerve Injuries / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D005838:Genotype; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D050797:STAT4 Transcription Factor / Q000235:genetics / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma