Single-cell analysis reveals T cell infiltration in old neurogenic niches

Ben W Dulken; Matthew T Buckley; Paloma Navarro Negredo; Naresha Saligrama; Romain Cayrol; Dena S Leeman; Benson M George; Stéphane C Boutet; Katja Hebestreit; John V Pluvinage; Tony Wyss-Coray; Irving L Weissman; Hannes Vogel; Mark M Davis; Anne Brunet

doi:10.1038/s41586-019-1362-5

Single-cell analysis reveals T cell infiltration in old neurogenic niches

Nature. 2019 Jul;571(7764):205-210. doi: 10.1038/s41586-019-1362-5. Epub 2019 Jul 3.

Authors

Ben W Dulken^#^{1

2

3}, Matthew T Buckley^#¹, Paloma Navarro Negredo^#¹, Naresha Saligrama^{4

5}, Romain Cayrol⁶, Dena S Leeman^{1

7

8}, Benson M George^{2

3}, Stéphane C Boutet^{9

10}, Katja Hebestreit^{1

11}, John V Pluvinage^{2

12}, Tony Wyss-Coray^{12

13}, Irving L Weissman³, Hannes Vogel⁶, Mark M Davis^{4

5

14}, Anne Brunet^{15

16}

Affiliations

¹ Department of Genetics, Stanford University, Stanford, CA, USA.
² Stanford Medical Scientist Training Program, Stanford University, Stanford, CA, USA.
³ Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
⁴ Department of Immunology and Microbiology, Stanford University, Stanford, CA, USA.
⁵ Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Cancer Biology Program, Stanford University, Stanford, CA, USA.
⁸ Immunology Discovery, Genentech, South San Francisco, CA, USA.
⁹ Fluidigm Corporation, South San Francisco, CA, USA.
¹⁰ 10x Genomics, Pleasanton, CA, USA.
¹¹ Verge Genomics, South San Francisco, CA, USA.
¹² Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Glenn Laboratories for the Biology of Aging at Stanford University, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁵ Department of Genetics, Stanford University, Stanford, CA, USA. abrunet1@stanford.edu.
¹⁶ Glenn Laboratories for the Biology of Aging at Stanford University, Stanford University School of Medicine, Stanford, CA, USA. abrunet1@stanford.edu.

^# Contributed equally.

Abstract

The mammalian brain contains neurogenic niches that comprise neural stem cells and other cell types. Neurogenic niches become less functional with age, but how they change during ageing remains unclear. Here we perform single-cell RNA sequencing of young and old neurogenic niches in mice. The analysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells and microglia, and an infiltration of T cells in old neurogenic niches. T cells in old brains are clonally expanded and are generally distinct from those in old blood, which suggests that they may experience specific antigens. T cells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon response shows decreased proliferation in vivo. We find that T cells can inhibit the proliferation of neural stem cells in co-cultures and in vivo, in part by secreting interferon-γ. Our study reveals an interaction between T cells and neural stem cells in old brains, opening potential avenues through which to counteract age-related decline in brain function.

MeSH terms

Aging / physiology*
Animals
Blood
Brain / cytology*
Cell Movement*
Cell Proliferation
Clone Cells / cytology
Coculture Techniques
Endothelial Cells / cytology
Interferon-gamma / metabolism
Male
Mice
Mice, Inbred C57BL
Microglia / cytology
Neural Stem Cells / cytology*
Neurogenesis*
Sequence Analysis, RNA
Signal Transduction
Single-Cell Analysis*
Stem Cell Niche / physiology*
T-Lymphocytes / cytology*
T-Lymphocytes / metabolism
Transcriptome / genetics

Substances

Interferon-gamma

Abstract

MeSH terms

Substances

Grants and funding