Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4

Laura Campisi (), Shahab Chizari, Jessica S. Y. Ho, Anastasia Gromova, Frederick J. Arnold, Lorena Mosca, Xueyan Mei, Yesai Fstkchyan, Denis Torre, Cindy Beharry, Marta Garcia-Forn, Miguel Jiménez-Alcázar, Vladislav A. Korobeynikov, Jack Prazich, Zahi A. Fayad, Marcus M. Seldin, Silvia Rubeis, Craig L. Bennett, Lyle W. Ostrow, Christian Lunetta, Massimo Squatrito, Minji Byun, Neil A. Shneider, Ning Jiang, Albert R. Spada () and Ivan Marazzi ()
Additional contact information
Laura Campisi: Icahn School of Medicine at Mount Sinai
Shahab Chizari: University of Pennsylvania
Jessica S. Y. Ho: Icahn School of Medicine at Mount Sinai
Anastasia Gromova: University of California, Irvine
Frederick J. Arnold: University of California, Irvine
Lorena Mosca: ASST Grande Ospedale Metropolitano Niguarda
Xueyan Mei: Icahn School of Medicine at Mount Sinai
Yesai Fstkchyan: Icahn School of Medicine at Mount Sinai
Denis Torre: Icahn School of Medicine at Mount Sinai
Cindy Beharry: Icahn School of Medicine at Mount Sinai
Marta Garcia-Forn: Icahn School of Medicine at Mount Sinai
Miguel Jiménez-Alcázar: Spanish National Cancer Research Centre
Vladislav A. Korobeynikov: Columbia University
Jack Prazich: University of Pennsylvania
Zahi A. Fayad: Icahn School of Medicine at Mount Sinai
Marcus M. Seldin: Center for Epigenetics and Metabolism, University of California, Irvine
Silvia Rubeis: Icahn School of Medicine at Mount Sinai
Craig L. Bennett: University of California, Irvine
Lyle W. Ostrow: Johns Hopkins University School of Medicine
Christian Lunetta: Fondazione Serena Onlus
Massimo Squatrito: Spanish National Cancer Research Centre
Minji Byun: Icahn School of Medicine at Mount Sinai
Neil A. Shneider: Columbia University
Ning Jiang: University of Pennsylvania
Albert R. Spada: University of California, Irvine
Ivan Marazzi: Icahn School of Medicine at Mount Sinai

Nature, 2022, vol. 606, issue 7916, 945-952

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-04844-5

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