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Microglia require CD4 T cells to complete the fetal to adult transition

ABSTRACT: The blood brain barrier has long been thought to isolate the brain from the adaptive immune system. While CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function at this site unknown. Here we have used a combination of imaging, single cell and surgical approaches to identify a unique CD69+ CD4 T cell population in both the mouse and human brain, which is distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells, and was shaped by interaction with the gut microbiome and self-antigen in the brain. Single cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between a fetal and adult state. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities in the adult mouse. These results illuminate a role for CD4 T cells in the basic developmental processes of the brain, and a potential interconnected dynamic between the evolution of the immunological and neurological systems.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146165 | GEO | 2020/07/27

REPOSITORIES: GEO

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Microglia require CD4 T cells to complete the fetal to adult transition

Project description:The blood brain barrier has long been thought to isolate the brain from the adaptive immune system. While CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function at this site unknown. Here we have used a combination of imaging, single cell and surgical approaches to identify a unique CD69+ CD4 T cell population in both the mouse and human brain, which is distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells, and was shaped by interaction with the gut microbiome and self-antigen in the brain. Single cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between a fetal and adult state. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities in the adult mouse. These results illuminate a role for CD4 T cells in the basic developmental processes of the brain, and a potential interconnected dynamic between the evolution of the immunological and neurological systems.

2020-07-27 | GSE144038 | GEO

Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (MS)

Project description:The human brain is populated by perivascular CD8+ and CD4+ T cells with a tissue-resident memory T (TRM)-cell phenotype. In multiple sclerosis (MS), these cells associate with white matter (WM) and, to a lesser extent, grey matter (GM) lesions. We here investigated the transcriptional and functional profile of brain-resident T cells. Of n=11 subsequent post-mortem brain donors, we isolated CD8+ and CD4+ effector memory and effector memory re-expressing CD45RA T cells from blood and CD8+ and CD4+ CD69+ T cells from corpus callosum WM and cortical GM. Additionally, brain CD69+ T cells were sorted from subcortical WM, corpus callosum WM, and medulla WM/GM of n=3–5 brain donors as well as from paired normal-appearing WM and GM and from WM and GM lesions of n=6 MS brain donors. In all donors, WM and GM T cells were overwhelmingly CD69+CD103+/-. Bulk RNA sequencing of CD8+ and CD4+ CD69+ T cells revealed TRM-cell signatures, as marked by differential expression of, among others, SELL (CD62L), ITGA1 (CD49a), and S1PR1. Notably, gene expression hardly differed between lesional and normal-appearing WM CD8+ and CD4+ CD69+ T cells in MS brains. Genes up-regulated in brain TRM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T-cell activity. In line with the increased presence of OPN in active MS lesions, we noticed a reduced production of the inflammatory cytokines IL-2, TNF, and IFNγ by MS lesion-derived CD8+ and CD4+ T cells ex vivo. This study discloses essential characteristics of human brain CD8+ and CD4+ TRM cells in non-MS and MS post-mortem WM and GM, reports OPN as a generic product of brain-resident immune cells, and shows a tight control of the activation state of TRM cells in MS lesions.

2022-12-05 | GSE216028 | GEO

Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter in Multiple Sclerosis (Location)

2022-12-05 | GSE216027 | GEO

Transcriptional profiling of brain CD4+ and CD8+ TRM cells reveals dominant presence in white and grey matter (Circulation)

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Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy subjects

Project description:Tissue-resident memory T cells (TRM) persist locally in non-lymphoid tissues where they provide front-line defense against recurring insults. TRM at barrier surfaces express the markers CD103 and/or CD69 which function to retain them in epithelial tissues. In humans, neither the long-term migratory behavior of TRM nor their ability to re-enter the circulation and potentially migrate to distant tissue sites have been investigated. Using tissue explant cultures, we found that CD4+CD69+CD103+ TRM in human skin can downregulate CD69 and exit the tissue. Additionally, we identified a skin-tropic CD4+CD69-CD103+ population in human lymph and blood that is transcriptionally, functionally and clonally related to the CD4+CD69+CD103+ TRM population in the skin. Using a skin xenograft model, we confirmed that a fraction of the human cutaneous CD4+CD103+ TRM population can re-enter circulation, and migrate to secondary human skin sites where they re-assume a TRM phenotype. Thus, our data challenge current concepts regarding the strict tissue compartmentalization of CD4+ T cell memory in humans.

2019-05-25 | GSE131770 | GEO

mRNA profiles of Salmonella specific tissue resident memory CD4 T cells and effector memory CD4 T cells from the liver, and splenic effector memory CD4 T cells

Project description:IFN -YFP reporter mice (Jax# 017580) were immunized intravenously with attenuated Salmonella enterica serovar Typhimurium intravenously. 45 days later, tissue resident memory CD4 T cells (CD69+ YFP+) in the liver, effector memory CD4 T cells (CD69- YFP+) in the liver, and effector memory CD4 T cells (CD69- YFP+) in the spleeen were sorted and RNA was sequenced

2022-09-17 | GSE211181 | GEO

CD69+ memory T lymphocytes of the bone marrow and spleen express the signature transcripts of tissue-resident memory T lymphocytes

Project description:To understand tissue resident features of memory CD4+ and CD8+ T lymphocytes of the bone marrow and/or spleen according to expressing or not the tissue retention marker CD69, we performed whole transcriptome profiling of ex vivo antigen-specific CD69+ and CD69- memory CD4+ T cells isolated from bone marrow and spleen, and ex vivo CD69+ and CD69- memory CD8+ T cells isolated from bone marrow.

2019-02-11 | GSE124796 | GEO

Protective function and differentiation cues of brain-resident CD8+ T cells during surveillance of latent Toxoplasma gondii infection

Project description:Chronic Toxoplasma gondii infection induces brain-resident CD8+ T cells (bTr) but the protective functions and differentiation cues of these cells remain undefined. Here, we used a mouse model of latent infection by T. gondii leading to effective CD8+ T cell-mediated parasite control. Thanks to antibody depletion approaches, we found that peripheral circulating CD8+ T cells are dispensable for brain parasite control during chronic stage, indicating that CD8+ bTr are able to prevent brain parasite reactivation. We observed that the retention markers CD69, CD49a and CD103 are sequentially acquired by brain parasite-specific CD8+ T cells throughout infection, and that a majority of CD69/CD49a/CD103 triple-positive (TP) CD8+ T cells also express Hobit, a transcription factor associated with tissue residency. This TP subset develops in a CD4+ T cell-dependent manner, and is associated with effective parasite control during chronic stage. Conditional invalidation of TAP-mediated MHC class I presentation showed that presentation of parasite antigens by glutamatergic neurons and microglia regulate the differentiation of CD8+ bTr into TP cells. Single-cell transcriptomic analyses revealed that resistance to encephalitis is associated with the expansion of stem-like subsets of CD8+ bTr. In summary, parasite-specific brain-resident CD8+ T cells are a functionally heterogeneous compartment which autonomously ensure parasite control during T. gondii latent infection and which differentiation is shaped by neuronal and microglial MHC I presentation. A more detailed understanding of local T cell-mediated immune surveillance of this common parasite is needed for harnessing brain-resident CD8+ T cells in order to enhance control of chronic brain infections.

2024-06-10 | GSE267427 | GEO

Characterization of young and aged lung tissue-resident influenza nucleoprotein-specific CD8 memory T cells

Project description:To identify the disparaties of D^b-nucleoprotein specific resident memory CD8 T cells between young and aged mice, we pooled n=11 aged or n=18 young lungs together after intraveounously labeling T cells and sorted ivCD90- CD8a+ CD44hi CD69+ D^b-NP tetramer (PE+ & APC+) cells. By scRNA-seq, we found the aged population was missing a cluster in the young population that resembled typical functional resident memory CD8 T cells indicating that aged resident memory CD8 T cells of this specificity would have poor recall function.

2020-10-06 | GSE159065 | GEO

Intrathymic T-cell selection

Project description:Comparisons between untreated primary cells T-cell precursors from the thymus. CD69- thymocytes are from Zap70-deficent mice and are >95% CD4+CD8+. These cells fail to generate intrathymic TCR signals as a result of their lacking Zap70 molecules, and are thus representative of "preselection" CD4+CD8+ thymocytes. The CD69hi population comes from wildtype mice and is heterogeneous for CD4 and CD8 expression. These cells have been intrathymically TCR-signaled and are undergoing selection.

2010-06-10 | E-GEOD-2262 | biostudies-arrayexpress

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