@article{c36eaf51fec9469ab369924d41f2bb6d,
title = "Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4",
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.",
author = "Laura Campisi and Shahab Chizari and Ho, {Jessica S.Y.} and Anastasia Gromova and Frederic Arnold and Lorena Mosca and Xueyan Mei and Yesai Fstkchyan and Denis Torre and Cindy Beharry and Marta Garcia-Forn and Miguel Jim{\'e}nez-Alc{\'a}zar and Korobeynikov, {Vladislav A.} and Jack Prazich and Fayad, {Zahi A.} and Seldin, {Marcus M.} and {De Rubeis}, Silvia and Bennett, {Craig L.} and Ostrow, {Lyle W.} and Christian Lunetta and Massimo Squatrito and Minji Byun and Shneider, {Neil A.} and Ning Jiang and {La Spada}, {Albert R.} and Ivan Marazzi",
note = "Funding Information: We thank N. Zhao and S. Zheng from the I.M. laboratory for critical inputs of the study; all the teams at ISMMS for sharing reagents; E. Drapeau for teaching the use of the rotarod; T. Kraus for use of the Luminex 100/200 plate reader; S. Cuadrado-Castano and A. Javaher for help with the B16 melanoma model; the Flow Cytometry and Mouse facilities for training and animal care, and the NGS Platform of the Center for Advanced Genomics Technology for SMART-sequencing; T. Dawson, D. D{\textquoteright}souza, B. Upadhyaya and all the team of the Human Immune Monitoring Center for CITE-sequencing and mass cytometry acquisition; and A. Soto, M. Garcia-Barros and the Biorepository and Pathology Dean{\textquoteright}s CoRE for assistance with histology. We are grateful to L. Manganaro, J. Moretti and A. Chan for their help in the preliminary phase of the project; M. J. Miller and M. F. Lavin for Setx-deficient mice; the Genomic and Microarray Core Facility of University of Texas Southwestern Medical Center for the autoantigen microarray analysis ; the Duke Electron Microscopy Service of the Duke University Pathology Core for ultrathin sections of axons; The Johns Hopkins ALS Postmortem Core and K. Wilsbach and K. Gallo for providing post-mortem human tissues; and the New York Blood Center for providing buffy coats. We are indebted to ALS4.org for help and support. This work was supported by The Burroughs Wellcome Fund 1017892 (I.M.); the Chan Zuckerberg Initiative Neurodegeneration Challenge Network: the Ben Barres Early Career Acceleration Awards (to I.M., 2018-191895, and N.J., 2018-191856 (5022)) and the Collaborative Science Award (to A.R.L.S., 108313-00002); the Hirschl Young Investigator fellowship (I.M.); National Institutes of Health grants U01AI150748, R01AI143840 and R01AI168130 (I.M.), T32 AI007647 and T32 HD075735 (Y.F.), R33CA225539 and R01AG067581 (N.J.), R35 NS122140 (A.R.L.S.), T32 AG00096 (F.A.), 5R01NS106236 (N.A.S.), R01HL153974 and U01AI150748 (M.B.); the start-up fund of the School of Engineering and Applied Science at University of Pennsylvania (N.J.); and ARISLA Italy, ALS Association ALSA, USA, and the Italian Ministry of Health CCM2011 (C.L.). M.S. received support from the Seve Ballesteros Foundation. J.S.Y.H. is supported by the Charles H Revson Foundation Biomedical Science Fellowship. M.G.-F. is a recipient of a post-doctoral fellowship from the Fundaci{\'o}n Alfonso Mart{\'i}n Escudero. Funding Information: We thank N. Zhao and S. Zheng from the I.M. laboratory for critical inputs of the study; all the teams at ISMMS for sharing reagents; E. Drapeau for teaching the use of the rotarod; T. Kraus for use of the Luminex 100/200 plate reader; S. Cuadrado-Castano and A. Javaher for help with the B16 melanoma model; the Flow Cytometry and Mouse facilities for training and animal care, and the NGS Platform of the Center for Advanced Genomics Technology for SMART-sequencing; T. Dawson, D. D{\textquoteright}souza, B. Upadhyaya and all the team of the Human Immune Monitoring Center for CITE-sequencing and mass cytometry acquisition; and A. Soto, M. Garcia-Barros and the Biorepository and Pathology Dean{\textquoteright}s CoRE for assistance with histology. We are grateful to L. Manganaro, J. Moretti and A. Chan for their help in the preliminary phase of the project; M. J. Miller and M. F. Lavin for Setx -deficient mice; the Genomic and Microarray Core Facility of University of Texas Southwestern Medical Center for the autoantigen microarray analysis ; the Duke Electron Microscopy Service of the Duke University Pathology Core for ultrathin sections of axons; The Johns Hopkins ALS Postmortem Core and K. Wilsbach and K. Gallo for providing post-mortem human tissues; and the New York Blood Center for providing buffy coats. We are indebted to ALS4.org for help and support. This work was supported by The Burroughs Wellcome Fund 1017892 (I.M.); the Chan Zuckerberg Initiative Neurodegeneration Challenge Network: the Ben Barres Early Career Acceleration Awards (to I.M., 2018-191895, and N.J., 2018-191856 (5022)) and the Collaborative Science Award (to A.R.L.S., 108313-00002); the Hirschl Young Investigator fellowship (I.M.); National Institutes of Health grants U01AI150748, R01AI143840 and R01AI168130 (I.M.), T32 AI007647 and T32 HD075735 (Y.F.), R33CA225539 and R01AG067581 (N.J.), R35 NS122140 (A.R.L.S.), T32 AG00096 (F.A.), 5R01NS106236 (N.A.S.), R01HL153974 and U01AI150748 (M.B.); the start-up fund of the School of Engineering and Applied Science at University of Pennsylvania (N.J.); and ARISLA Italy, ALS Association ALSA, USA, and the Italian Ministry of Health CCM2011 (C.L.). M.S. received support from the Seve Ballesteros Foundation. J.S.Y.H. is supported by the Charles H Revson Foundation Biomedical Science Fellowship. M.G.-F. is a recipient of a post-doctoral fellowship from the Fundaci{\'o}n Alfonso Mart{\'i}n Escudero. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = jun,
day = "30",
doi = "10.1038/s41586-022-04844-5",
language = "English",
volume = "606",
pages = "945--952",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7916",
}