Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease

David Gate; Naresha Saligrama; Olivia Leventhal; Andrew C Yang; Michael S Unger; Jinte Middeldorp; Kelly Chen; Benoit Lehallier; Divya Channappa; Mark B De Los Santos; Alisha McBride; John Pluvinage; Fanny Elahi; Grace Kyin-Ye Tam; Yongha Kim; Michael Greicius; Anthony D Wagner; Ludwig Aigner; Douglas R Galasko; Mark M Davis; Tony Wyss-Coray

doi:10.1038/s41586-019-1895-7

Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease

Nature. 2020 Jan;577(7790):399-404. doi: 10.1038/s41586-019-1895-7. Epub 2020 Jan 8.

Authors

David Gate^{1

2}, Naresha Saligrama³, Olivia Leventhal⁴, Andrew C Yang^{5

6}, Michael S Unger^{7

8}, Jinte Middeldorp^{4

9

10}, Kelly Chen⁴, Benoit Lehallier^{4

9}, Divya Channappa⁴, Mark B De Los Santos⁴, Alisha McBride^{4

9}, John Pluvinage^{4

11

12}, Fanny Elahi¹³, Grace Kyin-Ye Tam^{4

14}, Yongha Kim^{4

14}, Michael Greicius^{4

14}, Anthony D Wagner^{15

16}, Ludwig Aigner^{7

8}, Douglas R Galasko¹⁷, Mark M Davis^{3

18

19}, Tony Wyss-Coray^{20

21

22

23

24}

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. dgate@stanford.edu.
² Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA. dgate@stanford.edu.
³ Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA, USA.
⁴ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Bioengineering, Stanford University, Stanford, CA, USA.
⁶ Chemistry, Engineering and Medicine for Human Health, Stanford University, Stanford, CA, USA.
⁷ Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria.
⁸ Spinal Cord Injury and Tissue Regeneration Center Salzburg, Paracelsus Medical University, Salzburg, Austria.
⁹ Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA.
¹⁰ Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
¹¹ Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA.
¹² Stem Cell Biology and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Department of Neurology, Memory and Aging Center, University of California at San Francisco, San Francisco, CA, USA.
¹⁴ Functional Imaging in Neuropsychiatric Disorders Laboratory, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Department of Psychology, Stanford University, Stanford, CA, USA.
¹⁶ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
¹⁷ Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA.
¹⁸ Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.
²¹ Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA. twc@stanford.edu.
²² Chemistry, Engineering and Medicine for Human Health, Stanford University, Stanford, CA, USA. twc@stanford.edu.
²³ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. twc@stanford.edu.
²⁴ Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.

Abstract

Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function¹. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease². Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8⁺ T effector memory CD45RA⁺ (T_EMRA) cells. In a second cohort, we found that CD8⁺ T_EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8⁺ T_EMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

MeSH terms

Aged
Alzheimer Disease / immunology*
Amino Acid Sequence
CD8-Positive T-Lymphocytes / immunology*
Cerebrospinal Fluid / immunology*
Cohort Studies
Humans
Immunologic Memory
Middle Aged
Receptors, Antigen, T-Cell / chemistry
Receptors, Antigen, T-Cell / immunology
Sequence Analysis, Protein

Substances

Receptors, Antigen, T-Cell

Abstract

MeSH terms

Substances

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