TY - JOUR
T1 - Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4
AU - Campisi, Laura
AU - Chizari, Shahab
AU - Ho, Jessica S.Y.
AU - Gromova, Anastasia
AU - Arnold, Frederic
AU - Mosca, Lorena
AU - Mei, Xueyan
AU - Fstkchyan, Yesai
AU - Torre, Denis
AU - Beharry, Cindy
AU - Garcia-Forn, Marta
AU - Jiménez-Alcázar, Miguel
AU - Korobeynikov, Vladislav A.
AU - Prazich, Jack
AU - Fayad, Zahi A.
AU - Seldin, Marcus M.
AU - De Rubeis, Silvia
AU - Bennett, Craig L.
AU - Ostrow, Lyle W.
AU - Lunetta, Christian
AU - Squatrito, Massimo
AU - Byun, Minji
AU - Shneider, Neil A.
AU - Jiang, Ning
AU - La Spada, Albert R.
AU - Marazzi, Ivan
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/6/30
Y1 - 2022/6/30
N2 - Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.
AB - Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.
UR - http://www.scopus.com/inward/record.url?scp=85132581033&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-04844-5
DO - 10.1038/s41586-022-04844-5
M3 - Article
C2 - 35732742
AN - SCOPUS:85132581033
SN - 0028-0836
VL - 606
SP - 945
EP - 952
JO - Nature
JF - Nature
IS - 7916
ER -