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

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

doi:10.1038/s41586-019-1895-7

Cited by 616 publications

(702 citation statements)

References 30 publications

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“…Although it did not reach significance, a trend towards an increase in the presence of CD8 + T cells in the hippocampus of AD mice between weeks 2 and 6 was observed. This concords with recent observation of presence of CD8+ T cells in the hippocampi of AD human patients 24 .…”

Section: Discussionsupporting

confidence: 92%

The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression

Petitprez

Lévy

Sun

et al. 2020

Preprint

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129/150 words) 15Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for 16 various diseases, notably cancer. While numerous methods allow to quantify immune or stromal cells 17 in human tissue samples based on transcriptomic data, very few are available for mouse studies. 18Here, we introduce murine Microenvironment Cell Population counter (mMCP-counter), a method 19 based on highly specific transcriptomic markers that allow to accurately quantify 12 immune and 4 20 stromal murine cell populations. We validated mMCP-counter with flow cytometry data. We also 21 showed that mMCP-counter outperforms existing methods. We showed in mouse models of 22 mesothelioma and kidney cancer that mMCP-counter quantification scores are predictive of response 23 to immune checkpoint blockade Finally, we illustrated mMCP-counter's potential to analyze immune 24 impacts of Alzheimer's disease. mMCP-counter is available as an R package from GitHub: 25 https://github.com/cit-bioinfo/mMCP-counter.26 3 Main text (2,967 words) 27 28 Introduction 29 30 For a large number of diseases, such as inflammatory diseases or cancer, it is often crucial to 31 accurately determine the cellular composition of the tissue where the pathology develops, in terms of 32 immune and stromal cell populations. An array of methods are available to obtain these data from 33 human samples, either by immunochemistry or cytometry, or computationally from transcriptomics 34 data 1 . 35The analysis of the immune and stromal composition of tissues is particularly critical in cancer studies. 36Indeed, tumors are highly heterogeneous tissues which are infiltrated by a variety of immune and 37 stromal cells 2 . It was shown that immune cell densities were associated with prognosis 3 : For instance, 38CD8 + T cells density correlates with prolonged patient survival in most cancers, whereas M2-polarized 39 macrophages are generally associated with a poor prognosis 3 . 40The transcriptome of a bulk tissue sample yields the averaged expression of genes across all the cells 41 present in the sample. As some genes are uniquely expressed in some specific cell populations, their 42 expression can be used to determine the abundance of the underlying cell populations. Using this 43 property, we have previously reported on MCP-counter, a method designed to quantify the immune 44 infiltrate of heterogeneous human tissues 4 , currently one of the best performing methods for this 45 purpose 5 . 46While murine models are widely used to decipher the pathophysiological mechanisms of various 47 diseases, including inflammatory diseases and cancer, the computational methods currently available 48 to measure the immune and stromal composition of murine tissues are few and limited, as compared 49 to what is available for human samples 6 . 50Here, we introduce murine Microenvironment Cell Populations counter (mMCP-counter), the 51 adaptation of the MCP-counter method to murine samples (Figure 1), which was made possible 52 thanks to the release o...

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Section: Discussionsupporting

confidence: 92%

The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression

Petitprez

Lévy

Sun

et al. 2020

Preprint

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“…The role of MHC class 1 molecules in the CNS has yet to be fully characterized but appears to participate in developmental synaptic pruning (Lee et al, 2014) as well as the adaptive immune response. Alterations in MHC expression are a consistent observation in neurodegenerative disorders including Alzheimer's disease, where they may contribute to synaptic dysfunction and altered T cell recruitment (Gate et al, 2020). Our discovery of species differences in astrocyte immune signaling has important implications for mouse models of neurodegeneration and may guide opportunities to enhance mechanistic understanding where mouse models display limited toxicity to human disease mutations and pathologies.…”

Section: The Conservation and Divergence Of Human And Mouse Astrocytementioning

confidence: 89%

Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes

Pan

Godoy

et al. 2020

Preprint

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Human-mouse differences are a major barrier in translational research.Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration. However, the similarities and differences between human and mouse astrocytes are largely unknown. Combining analyses of acutely purified astrocytes, experiments using serum-free cultures of primary astrocytes, and xenografted chimeric mice, we found extensive conservation in astrocytic gene expression between human and mouse. However, genes involved in defense response and metabolism showed species differences. Human astrocytes exhibited greater susceptibility to oxidative stress than mouse astrocytes, due to differences in mitochondria physiology and detoxification pathways. Mouse astrocytes, but not human astrocytes, activate a molecular program for neural repair under hypoxia. Human astrocytes, but not mouse astrocytes, activate the antigen presentation pathway under inflammatory conditions. These species-dependent properties of astrocytes may contribute to differences between mouse models and human neurological and psychiatric disorders.

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“…Second, what recruits and activates T cells to the brain, and how does it do so? So far, T cells are rarely detected in brain parenchyma and mostly are restricted to the borders of the brain, particularly the choroid plexus and brain meninges and, in few cases, the cerebrospinal fluid that surrounds the brain and spinal cord due to breakdown 13 of the blood-brain barrier (Dulken et al, 2019;Filiano et al, 2016;Gate et al, 2020;Ito et al, 2019;Keren-Shaul et al, 2017;Lodygin et al, 2019;Sun et al, 2018). It remains mostly unknown which factors trigger the recruitment of T cells to the brain.…”

Section: Discussionmentioning

confidence: 99%

“…It remains mostly unknown which factors trigger the recruitment of T cells to the brain. One study of Alzheimer's disease (Gate et al, 2020) found that T cells bound two antigens produced by Epstein-Barr virus. However, no report so far has connected Epstein-Barr virus infection to neurodegeneration (Heneka, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…However, most studies have focused on the nonspecific, innate immune cells (mostly microglia) (Heneka et al, 2013;Hong et al, 2016;Ising et al, 2019;Ito et al, 2016;Keren-Shaul et al, 2017;Labzin et al, 2018;Singhal et al, 2014;Xu et al, 2018). More recently, a few of reports revealed T cells' contributions to NDs (Gate et al, 2020;Jelcic et al, 2018;Lodygin et al, 2019;Shichita et al, 2009;Sulzer et al, 2017;Sun et al, 2018). Accumulated evidence suggests that the neurodegenerative process involves communication and interaction among neurons, microglia, astrocytes and immune cells (including T cells and other innate or adaptive cells).…”

Section: Introductionmentioning

confidence: 99%

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Arf1-Ablation-Induced Neuronal Damage Promotes Neurodegeneration Through an NLRP3 Inflammasome–Meningeal γδ T cell–IFNγ-Reactive Astrocyte Pathway

Wang

Shin

2020

Preprint

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Neurodegenerative diseases are often initiated from neuronal injury or disease and propagated through neuroinflammation and immune response. However, the mechanisms by which injured neurons induce neuroinflammation and immune response that feedback to damage neurons are largely unknown. Here, we demonstrate that Arf1 ablation in adult mouse neurons resulted in activation of a reactive microglia-A1 astrocyte-C3 pathway in the hindbrain and midbrain but not in the forebrain, which caused demyelination, axon degeneration, synapse loss, and neurodegeneration. We further find that the Arf1-ablated neurons released peroxided lipids and ATP that activated an NLRP3 inflammasome in microglia to release IL-1β, which together with elevated chemokines recruited and activated γδT cells in meninges. The activated γδ T cells then secreted IFNγ that entered into parenchyma to activate the microglia-A1 astrocyte-C3 neurotoxic pathway for destroying neurons and oligodendrocytes. Finally, we show that the Arf1-reductioninduced neuroinflammation-IFNγ-gliosis pathway exists in human neurodegenerative diseases, particularly in amyotrophic lateral sclerosis and multiple sclerosis. This study illustrates perhaps the first complete mechanism of neurodegeneration in a mouse model.Our findings introduce a new paradigm in neurodegenerative research and provide new opportunities to treat neurodegenerative disorders.

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

Cited by 616 publications

References 30 publications

The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression

The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression

Conservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes

Arf1-Ablation-Induced Neuronal Damage Promotes Neurodegeneration Through an NLRP3 Inflammasome–Meningeal γδ T cell–IFNγ-Reactive Astrocyte Pathway

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