A CD8 T cell signature in ALS4.

Abstract Motor neuron disorders (MND) cause disability and death globally. Despite an increasing knowledge of the genetic defects of MND, a clear understanding of the mechanisms of disease initiation and progression is lacking. Recent advance in the field has highlighted that several genes linked to MND are essential for maintaining immune homeostasis, suggesting that dysfunctions in the immune system could influence the development of the disease or aggravate its pathology. Amyotrophic Lateral Sclerosis 4 (ALS4) is a rare, juvenile form of MND. It is caused by mutations in the gene SENATAXIN (SETX), which encodes for a nuclear helicase ubiquitously expressed. Our group identified SETX as a transcriptional regulator of inflammatory responses. Since SETX is involved in both MND and the control of the immune response, we hypothesized that underlying defects in the immune system could be associated to ALS4 progression. We took advantage of the Setx-L389S+/− knock-in (KI) mouse carrying the most common causative variant of ALS4 in humans. Surprisingly, we found that SetxL389S needs to be expressed in both neuronal and immune cells to trigger disease. In parallel, we discovered a pathologic signature consisting of high frequencies of activated CD8 T cells in the central nervous system (CNS) and blood of KI animals. Further analyses showed clonal expansion of aberrant activated CD8 T cells. Dysfunctions in the CD8 T cell compartment have been confirmed in the peripheral blood of ALS4 patients, as compared to age-matched controls. Collectively, our results suggest that ALS4 is characterized by aberrant CD8 T cell responses of possible autoimmune origin. Our findings have the potential to pave the way for immune-based diagnosis and therapy for patients.