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

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

doi:10.1038/s41586-019-1362-5

Cited by 367 publications

(413 citation statements)

References 65 publications

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“…Aging and Alzheimer's disease (AD) produce widespread effects on the central nervous system (CNS) that are characterized by cognitive decline, vulnerability to physical illnesses, elevated oxidative stress, and chronic brain inflammation [1]. These biological and pathological processes are also associated with diminished blood-brain barrier (BBB) integrity, which leads to the accumulation in the brain of blood-derived proteins [2,3] and the infiltration of peripheral cells [4][5][6][7][8][9], and multiple lines of evidence indicate that the innate-immune functions of microglia and astrocytes are involved in these processes.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of microglia and astrocytes throughout aging

Pan

et al. 2020

J Neuroinflammation

111

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Background: Activation of microglia and astrocytes, a prominent hallmark of both aging and Alzheimer's disease (AD), has been suggested to contribute to aging and AD progression, but the underlying cellular and molecular mechanisms are largely unknown. Methods:We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and APP-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles.Results: Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). And most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes.Conclusions: Overall, our RNA-seq data provide a valuable resource for future investigations into the roles of microglia and astrocytes in aging-and amyloid-β-induced AD pathologies.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of microglia and astrocytes throughout aging

Pan

et al. 2020

J Neuroinflammation

111

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“…Ageing is accompanied by immune dysfunction and a paradoxical increase of cytokines in several tissues, including the brain 51 . A recent study conducted in mice demonstrates a clonal T cell expansion within the brain of old mice with high levels of IFN-γ, suggesting a role for T cellderived IFN-γ in the age-dependent decline of brain function 65 . Given the presence of T lymphocytes in PD brains and the increasing evidence pointing towards a role for T cell responses in disease pathogenesis 66,67,68 , T-cells could be the main source of IFN-γ, which, in turn, induces LRRK2 expression in neurons and microglia, leading to neuronal damage and inflammatory reactions.…”

Section: Discussionmentioning

confidence: 99%

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

Cicco

Ivanyuk

Haq

et al. 2020

Preprint

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Increasing evidence suggests a role for interferons (IFNs) in neurodegeneration.Parkinson's disease (PD) associated kinase LRRK2 has been implicated in IFN type II (IFN) response in infections and nigral neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ still remains unclear. Here, we employed dopaminergic (DA) neurons and microglia differentiated from patient induced pluripotent stem cells to unravel the role of IFN-γ in LRRK2-PD. We show that IFN-γ induces LRRK2 expression in both DA neurons and microglial cells. LRRK2-G2019S, the most common PD-associated mutation, sensitizes DA neurons to IFN-γ by decreasing AKT phosphorylation. IFN-γ suppresses NFAT activity in both neurons and microglia and synergistically enhances LRRK2-induced defects of NFAT activation.Furthermore, LRRK2-G2019S negatively regulates NFAT via calcium and microtubule dynamics. Importantly, we uncover functional consequences of the reduction of NFAT activity in both cell types, namely defects of neurite elongation and alteration of microglial activation profile and motility. We propose that synergistic IFN-γ/LRRK2 activation serves as a direct link between inflammation and neurodegeneration in PD.

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“…NGS approaches for generating immune repertoires commonly begin with genomic DNA or mRNA and produce high-depth bulk repertoires of unpaired immunoglobulin or T cell receptor V(D)J sequences (33)(34)(35). Recent approaches use single-cell isolation techniques with highthroughput sequencing to construct repertoires, sometimes with paired gene expression (36)(37)(38)(39). These include studies on tumor-infiltrating lymphocytes from cancer biopsies, infiltrates from the brain of mice and B cells from the spleen after vaccination in mice; no such studies have investigated the circulating B cell repertoire in patients with autoimmune disease thusfar (37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

“…Recent approaches use single-cell isolation techniques with highthroughput sequencing to construct repertoires, sometimes with paired gene expression (36)(37)(38)(39). These include studies on tumor-infiltrating lymphocytes from cancer biopsies, infiltrates from the brain of mice and B cells from the spleen after vaccination in mice; no such studies have investigated the circulating B cell repertoire in patients with autoimmune disease thusfar (37)(38)(39). Previous immune repertoire studies of BCDT have identified persistent expanded clones and associations between clonality and responder status, and single-cell transcriptome studies have recapitulated flow cytometry results showing increased frequencies of antigen-experienced B cells at the peak of depletion (32,(40)(41)(42).…”

Section: Introductionmentioning

confidence: 99%

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

Jiang

Fichtner

Hoehn

et al. 2019

Preprint

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One Sentence Summary: Disease relevant B cells during post-rituximab (RTX) relapse emerge from the unsuccessful depletion of pre-existing B cell clones; single-cell transcriptomic phenotyping combined with lineage tracing using paired B cell receptor repertoires identified both persistent antibody-secreting cell as well as memory B cell subsets.Abstract: Rituximab, an anti-CD20 B cell-depleting therapy, is indicated to treat a growing number of autoimmune disorders. However, disease relapses can occur when the B cell compartment is re-established after treatment. To explore the mechanism of relapse, we studied patients with muscle-specific kinase (MuSK) myasthenia gravis (MG), a paradigm for B cellmediated autoimmune diseases in which pathology is directly associated with autoantibody production. Whether the failed depletion of specific clones leads to the persistence of autoantibody producing B cell subsets has yet to be elucidated. Here we show that rituximab (RTX) therapy is not fully effective at eliminating disease-associated B cells and provide a mechanistic understanding of relapse. We carried out single-cell transcriptional and B cell receptor (BCR) profiling on longitudinal B cell samples from the peripheral blood of MuSK MG patients who relapsed after rituximab therapy. Computational analysis of these data identified individual B cells that were refractory to rituximab depletion by linking them to clones that were present prior to therapy and continued to persist after therapy. These persistent B cell clones were present at high frequency, and included both antibody-secreting cells and memory B cells. They were disproportionately isotype switched with elevated somatic hypermutation frequencies and a gene expression signature associated with antigen-experience and B cell clonal expansion. We further identified both antibody-secreting cells and memory B cells with specificity for MuSK autoantigen that were clonally expanded during relapse and persistent. Our results provide evidence that post-rituximab relapse in MuSK MG is associated with the failed depletion of autoantigen-specific B cell subsets. This work provides insight into the durability of human B cells during treatment with therapeutic CD20-specific monoclonal antibodies. The transcriptional signatures associated with B cell resistance may represent new therapeutic avenues for treatment and biomarkers of depletion efficacy.

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

Cited by 367 publications

References 65 publications

Transcriptomic profiling of microglia and astrocytes throughout aging

Transcriptomic profiling of microglia and astrocytes throughout aging

Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia

Single-cell repertoire tracing identifies rituximab refractory B cells during myasthenia gravis relapses

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