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

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. DavisTony Wyss-Coray

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

558 Scopus citations

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.

Original language	English (US)
Pages (from-to)	399-404
Number of pages	6
Journal	Nature
Volume	577
Issue number	7790
DOIs	https://doi.org/10.1038/s41586-019-1895-7
State	Published - Jan 16 2020

Funding

Acknowledgements We thank M. Leipold, S. Douglas and H. Maecker from the Stanford Human Immune Monitoring Core for helpful discussion and assistance with mass cytometry experiments; B. Dulken and A. Brunet of Stanford University for sharing related mouse research; B. Carter of the Palo Alto Veterans Affairs FACS facility; V. Henderson and the entire Stanford Alzheimer's disease Reserach Center team; G. Kerchner and S. Sha for CSF collection; G. Deutsch, C. Litovsky and M. Thieu for assistance with cognitive assessments; and V. Carr, S. Guerin, A. Trelle and the Stanford Aging and Memory Study (SAMS) team for MRI data collection. This work was supported by a Glenn/American Federation for Aging Research (AFAR) Postdoctoral Fellowship for the Biology of Aging (D.G.), a National Institutes of Health National Institute on Aging (NIA) F32 Fellowship (AG055255-01A1) (D.G.), an Irene Diamond Fund/AFAR Postdoctoral Transition Award in Aging (D.G.), a National Multiple Sclerosis Society Postdoctoral Fellowship (N.S.), the National Institutes of Health Institute for Allergy, Infectious Diseases and Immunology (U19-AI057229), the Howard Hughes Medical Institute (N.S. and M.M.D.), the Austrian Science Funds Special Research Program F44 (F4413-B23) (M.S.U.), NIA R01 AG048076 (A.D.W.), the Dana Foundation (A.D.W.), the Cure Alzheimer’s Fund (T.W.-C.), the NOMIS Foundation (T.W.-C.), the Stanford Brain Rejuvenation Project (an initiative of the Stanford Neurosciences Institute), NIA R01 AG045034 05 (T.W.-C.) and the NIA funded Stanford Alzheimer’s Disease Research Center (P50AG047366).

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Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., Chen, K., Lehallier, B., Channappa, D., De Los Santos, M. B., McBride, A., Pluvinage, J., Elahi, F., Tam, G. K. Y., Kim, Y., Greicius, M., Wagner, A. D., Aigner, L., Galasko, D. R., ... Wyss-Coray, T. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature, 577(7790), 399-404. https://doi.org/10.1038/s41586-019-1895-7

@article{04d25c1c9764450ca8e45259346aeea5,

title = "Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer{\textquoteright}s disease",

abstract = "Alzheimer{\textquoteright}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{\textquoteright}s disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer{\textquoteright}s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer{\textquoteright}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{\textquoteright}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{\textquoteright}s disease to two separate Epstein–Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer{\textquoteright}s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.",

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

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

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month = jan,

day = "16",

doi = "10.1038/s41586-019-1895-7",

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Gate, D, Saligrama, N, Leventhal, O, Yang, AC, Unger, MS, Middeldorp, J, Chen, K, Lehallier, B, Channappa, D, De Los Santos, MB, McBride, A, Pluvinage, J, Elahi, F, Tam, GKY, Kim, Y, Greicius, M, Wagner, AD, Aigner, L, Galasko, DR, Davis, MM & Wyss-Coray, T 2020, 'Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease', Nature, vol. 577, no. 7790, pp. 399-404. https://doi.org/10.1038/s41586-019-1895-7

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T1 - Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease

AU - Gate, David

AU - Saligrama, Naresha

AU - Leventhal, Olivia

AU - Yang, Andrew C.

AU - Unger, Michael S.

AU - Middeldorp, Jinte

AU - Chen, Kelly

AU - Lehallier, Benoit

AU - Channappa, Divya

AU - De Los Santos, Mark B.

AU - McBride, Alisha

AU - Pluvinage, John

AU - Elahi, Fanny

AU - Tam, Grace Kyin Ye

AU - Kim, Yongha

AU - Greicius, Michael

AU - Wagner, Anthony D.

AU - Aigner, Ludwig

AU - Galasko, Douglas R.

AU - Davis, Mark M.

AU - Wyss-Coray, Tony

PY - 2020/1/16

Y1 - 2020/1/16

N2 - 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.

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

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