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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

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

Project description:Microglia require CD4 T cells to complete the fetal to adult transition

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

Project description:Microglia require CD4 T cells to complete the fetal to adult transition

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Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection

Project description:Mucosal barrier surfaces serve as the critical first line of defense separating our bodies from the plethora of pathogenic microorganisms that inhabit our environment. Adaptive immunity provides life-long protection through the generation of a central and effector memory T-cell pool, memory B cells and the recently described population of tissue resident memory cells (TRM). The cellular origin of TRM CD4 cells is unknown and the contribution of this CD4 memory population to host defense still remains elusive. By using IL-17A tracking-fate-mouse models we found that a significant fraction of the CD4 TRM cells derive from IL-17A producing effector (TH17) cells following primary immunization. Maintenance of these resting exTH17 TRM cells is mediated by IL-7, produced by lymphatic endothelial cells. During a memory response, we show that neither antibodies, nor gd T cells, nor circulatory memory T cells are sufficient for the rapid host defense required to eliminate the pathogen. Using parabiosis and depletion studies, we demonstrated that CD4 exTH17 TRM cells play an important role in respiratory defense and bacterial clearance. Upon infection, exTH17 TRM cells rapidly produce IL-17A and IFN-γ to promote neutrophil infiltration and bacterial clearance. These studies delineate the origin, function and importance of airway CD4 TRM cells during bacterial infection, offering novel strategies for targeted vaccine design, which is especially imperative for those pathogens that are resistant to antibiotic treatment.

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Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection

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Skin Resident Memory CD4+ T Cells Enhance Protection Against Leishmania Major Infection

Project description:Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection following disease resolution, effective immune protection has not yet been achieved by human vaccines. While circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFNγ, and remain resident in the skin when transplanted by skin graft onto naïve mice. They function to recruit circulating T cells to the skin in a CXCR3 dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells. Two conditions were analyzed. For each condition, four mice were used, resulting in eight samples in total.

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

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 | GSE216026 | GEO

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

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 for lung tissue-resident helper T cell and spleen follicular T cells

Project description:We reported hybrid CD4+ T cell population following influenza viru infection. The hybrid CD4+ T cells exhibit both tissue residency and follicular helper T cell features. To further charaterization, we sorted lung tissue-resident helper T (TRH or TTH) cells (CD45iv-CD4+CD44+GITR-PD1hiFR4hi), non-TRH (CD45iv-CD4+CD44+GITR-PD1lowFR4low), spleen follicalar helper T (TFH) cells (CD4+CD44+GITR-PD1hiCXCR5hi) and non-TFH cells (CD4+CD44+GITR-PD1lowCXCR5low). Then the cells were applied for RNA sequencing. At the resut, we showed tissue-residency related genes are highly enriched in lung TRH but not spleen TFH cells. And The lung TRH cells express higher levels of TFH-related genes than lung-non TRH cells. Therefore, we suggest TRH cells play a role as tissue-resident helper T cells.

2020-11-27 | GSE153226 | GEO

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