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.
David Gate  1  2 ,  Naresha Saligrama  3 ,  Olivia Leventhal  4 ,  Andrew C Yang  5  6 ,  Michael S Unger  7  8 ,  Jinte Middeldorp  4  9  10 ,  Kelly Chen  4 ,  Benoit Lehallier  4  9 ,  Divya Channappa  4 ,  Mark B De Los Santos  4 ,  Alisha McBride  4  9 ,  John Pluvinage  4  11  12 ,  Fanny Elahi  13 ,  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 Galasko  17 ,  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. [email protected].
  • 2. Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA. [email protected].
  • 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. [email protected].
  • 21. Veterans Administration Palo Alto Healthcare System, Palo Alto, CA, USA. [email protected].
  • 22. Chemistry, Engineering and Medicine for Human Health, Stanford University, Stanford, CA, USA. [email protected].
  • 23. Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. [email protected].
  • 24. Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
PMID: 31915375 DOI: 10.1038/s41586-019-1895-7
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+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA 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+ TEMRA 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.