CD4 T cell‐mediated neuroprotection: Relevence to ALS and Motoneuron Injury

Abstract

We have identified a beneficial role for the peripheral immune system in motoneuron reparative processes through use of the mouse facial motoneuron (FMN) injury paradigm, which involves a peripheral nerve injury outside the blood‐brain‐barrier, in conjunction with immunodeficient mouse models (including the recombinase‐activating gene‐2 knockout (RAG‐2KO) mouse which lacks functional T and B cells; Serpe et al., 1999). We initially focused on understanding the mechanism by which the immune system FMN survival following injury. Accomplishments thus far include the identification of the CD4+ effector Th2 cell as the critical cell needed for FMN rescue from axotomy‐induced cell death through an antigen‐specific process requiring peripheral activation followed by central re‐activation and brain‐derived neurotrophic factor (BDNF) as the molecule required for Th2 cell‐mediated FMN rescue. Although the CD4+ effector Th1 cell is not required for FMN rescue, lymph node analysis indicates that both a Th1 and Th2 cytokine profile develops in response to peripheral nerve injury. We also have determined that functional recovery from facial paralysis induced by facial nerve crush injury is significantly impaired in immunodeficient animals, but is restored to wild‐type (WT) after reconstitution of the immune system. Collectively, these findings provide the foundation for a working model of CD4+T cell‐mediated motoneuron survival and axonal regeneration after injury. Key to this model is the new concept that CD4+ effector T cell subsets play distinctive roles in motoneuron reparative processes, with the Th2 cell mediating FMN survival through a central BDNF‐dependent process and the Th1 cell mediating functional recovery through participation in the lesion site pro‐inflammatory response. How this concept may be applied to the disease process of ALS, a fatal motoneuron disease, will be discussed.