Immune-mediated neuroprotection of axotomized mouse facial motoneurons is dependent on the IL-4/STAT6 signaling pathway in CD4+ T cells

Abstract

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-γ) or the Th2 cytokine IL-4 is involved in mediating FMN survival, facial nerve axotomy was applied to IFN-γ−/− and IL-4−/− mice. A significant decrease in FMN survival after axotomy occurred in IL-4−/− but not in IFN-γ−/− mice compared to WT mice, indicating that IL-4 but not IFN-γ is important for FMN survival after nerve injury. In WT mice, intracellular IFN-γ 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.