We read with interest the opinion of Walsh and Kipnis on the roles played by regulatory T CD4+CD25+Foxp3+ cells (Treg) in neurodegenerative diseases [1]. Although we agree that Tregs play a multifaceted complex role in disease, we hold divergent views on the importance of the cells as neuroprotective agents for central nervous system (CNS) immunity. Indeed, recent studies performed in our own laboratories demonstrated that Treg cells play critical roles in controlling the tempo of both amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) and that such biologic events parallel what is reported in other autoimmune and cancerous diseases [2–7]. Importantly, induction of Treg commonly leads to improved disease outcomes in animal models of human neurodegenerative disorders [3, 4]. Although extrapolating from animal models to human disease is complex, the lack of effective neuroprotective therapy for ALS and PD urges the translation of Treg immunomodulatory therapeutic approaches for treatment of human neurodegenerative disorders [8].

Neuroimmunity: complex not confused The role played by Treg in ALS and PD is not dissimilar to what is observed in peripheral wound repair. As in the periphery, the innate and the adaptive immune systems play essential roles in the maintenance of CNS homeostasis in both health and disease. The major resident innate immune cells are the microglia, which constantly survey the microenvironment through continuous extension, retraction and remodeling of their cellular processes [9]. Similar to peripheral macrophages, microglia have diverse phenotypic states spanning the spectrum from an alternatively activated [10] M2 protective phenotype producing anti-inflammatory cytokines and neurotrophic factors to a classically activated M1 toxic phenotype producing reactive oxygen species (ROS) and proinflammatory cytokines. Following tissue damage, microglia [11] undergo rapid morphological and functional activation and promote an inflammatory response that enlists the adaptive immune system in an effort to initiate tissue repair; in addition, T cells and blood-borne macrophages enter from the periphery to help restore tissue homeostasis and sustain neuronal viability.