SOD1G93A transgenic mouse CD4+ T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment

摘要

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving motoneuron (MN) axonal withdrawal and cell death. Previously, we established that facial MN (FMN) survival levels in the SOD1^G93A transgenic mouse model of ALS are reduced and nerve regeneration is delayed, similar to immunodeficient RAG2^-/- mice, after facial nerve axotomy. The objective of this study was to examine the functionality of SOD1^G93A splenic microenvironment, focusing on CD4⁺ T cells, with regard to defects in immune-mediated neuroprotection of injured MN. We utilized the RAG2^-/- and SOD1^G93A mouse models, along with the facial nerve axotomy paradigm and a variety of cellular adoptive transfers, to assess immune-mediated neuroprotection of FMN survival levels. We determined that adoptively transferred SOD1^G93A unfractionated splenocytes into RAG2^-/- mice were unable to support FMN survival after axotomy, but that adoptive transfer of isolated SOD1^G93A CD4⁺ T cells could. Although WT unfractionated splenocytes adoptively transferred into SOD1G93A mice were able to maintain FMN survival levels, WT CD4⁺ T cells alone could not. Importantly, these results suggest that SOD1^G93A CD4⁺ T cells retain neuroprotective functionality when removed from a dysfunctional SOD1^G93A peripheral splenic microenvironment. These results also indicate that the SOD1^G93A central nervous system microenvironment is able to re-activate CD4⁺ T cells for immune-mediated neuroprotection when a permissive peripheral microenvironment exists. We hypothesize that dysfunctional SOD1^G93A peripheral splenic microenvironment may compromise neuroprotective CD4⁺ T cell activation and/or differentiation, which, in turn, results in impaired immune-mediated neuroprotection for MN survival after peripheral axotomy in SOD1^G93A mice.