Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE56575 | GEO | 2014/05/13
SECONDARY ACCESSION(S): PRJNA243939
REPOSITORIES: GEO
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Project description:Neonates often generate incomplete immunity against intracellular pathogens, although the mechanism of this defect is poorly understood. An important question is whether the impaired development of memory CD8+ T cells in neonates is due to an immature priming environment or lymphocyte-intrinsic defects. Here we show that neonatal and adult CD8+ T cells adopted different fates when responding to equal amounts of stimulation in the same host. While adult CD8+ T cells differentiated into a heterogeneous pool of effector and memory cells, neonatal CD8+ T cells preferentially gave rise to short-lived effector cells and exhibited a distinct gene expression profile. Surprisingly, impaired neonatal memory formation was not due to a lack of responsiveness, but instead because neonatal CD8+ T cells expanded more rapidly than adult cells and quickly became terminally differentiated. Collectively, these findings demonstrate that neonatal CD8+ T cells exhibit an imbalance in effector and memory CD8+ T cell differentiation, which impairs the formation of memory CD8+ T cells in early life mRNA profiles of effector CD8+ T cells from neonatal and adult mice
2014-05-13 | E-GEOD-56575 | biostudies-arrayexpress
Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. Small RNAs were sequenced from adult and neonatal CD8+ T cells before and during infection
2015-09-24 | E-GEOD-65920 | biostudies-arrayexpress
Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. Small RNAs were sequenced from adult and neonatal CD8+ T cells before infection.
2015-09-24 | E-GEOD-66650 | biostudies-arrayexpress
Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. PolyA RNA was selected and sequenced from adult and neonatal CD8+ T cells before and during infection
2015-09-24 | E-GEOD-65921 | biostudies-arrayexpress
Project description:Neonates are intrinsically defective at creating memory CD8+ T cells in response to infection with intracellular pathogens. Here we investigated differential of small RNAs, transcription factors, and chemokine receptors regulation in neonates as compared to adults before and during infection. We found that prior to infection, naïve cells have a different expression profile for many microRNAs, and gene targets of these microRNAs show widespread expression differences. These targets and other changes in gene expression in naïve cells result in neonatal cells that get activated more easily, express chemokine receptors that home to sites of infection, and are less protected from apoptosis during contraction. As a result, changes in neonatal naïve cells drive effector cell terminal differentiation at the expense of creating long-lived memory cells. total RNAs were sequenced from adult and neonatal CD8+ T cells before and during infection
2015-09-24 | E-GEOD-65922 | biostudies-arrayexpress
Project description:<p>The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving the changes characteristic of immune aging in humans remain poorly understood. One hallmark of immune aging is the loss of self-renewing naive cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we first inferred the transcription factor binding activities that maintain the naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we determined that BATF, ETS1, Eomes, and Sp1 govern transcription networks associated with specific CD8 T cell subset properties, including activation and proliferative potential. Extending our analysis to aged humans, we found that the differences between memory and naive CD8 T cells were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward a more differentiated pattern of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin openness at gene promoters, a phenomenon that appears to be due largely to a loss in binding by NRF1, leading to a marked drop-off in the ability of the naive cell to initiate transcription of mitochondrial genes. Our findings identify BATF- and NRF1-driven gene regulation as targets for delaying CD8 T cell aging and restoring T cell function.</p>
| phs001187 | dbGaP
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
2021-11-08 | GSE159684 | GEO
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
2021-11-08 | GSE159687 | GEO
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
2021-11-08 | GSE159686 | GEO
Project description:Neonates are highly susceptible to repeat infection and respond poorly to vaccination; these attributes derive from intrinsic differences between neonatal and adult naïve CD8+ T cells. In contrast to adult cells, naïve neonatal cells exhibit a greatly limited ability to differentiate into memory cells, a fundamental property of their adult counterparts. Here, we describe the role of the miR-29 microRNA in naïve T cells, focusing on age-related differences in miR-29 expression and the consequences of these differences in adult and neonatal cells, from mice and humans. In adults, high expression of miR-29 licenses naïve cells towards eventual memory cell fates; whereas neonatal naïve cells, which lack high expression of miR-29, are predisposed towards effector cell fates in response to an infection. Multiple lines of evidence support this model, including analysis of a mouse model deficient in miR-29, which we examine with adoptive transfer experiments to define the functional consequences of reduction of miR-29, together with genomic assays to define the regulatory impact of miR-29. Adult miR 29 deficient naïve CD8+ T cells cell are primed for activation and therefore secrete elevated levels of cytolytic molecules, and express transcription factors at levels associated with effector cell differentiation; moreover, these cells exhibit an altered CD8+ T cell memory repertoire, akin to that of neonatal CD8+ T cells. Importantly, we use a method that exploits extracellular vesicles as a delivery vehicle with which to modulate levels of miR-29 in neonatal and adult naïve T cells, examining both human and mouse cells. For example, increasing miR 29 expression in mouse naïve neonatal CD8+ T cells significantly improved the memory response during infection, concomitant with alterations to the chromatin landscape characteristic of cells primed for memory differentiation. Delivery of miR-29 antagomirs to human adult naïve CD8+ T cells was sufficient to induce the adult cells to adopt phenotypes and gene expression signatures normally found in cells present in newborns. This study establishes miR-29 as a key conserved regulator in naïve CD8+ T cells, and by adjusting levels of miR-29, has the potential to underlie therapeutic strategies for controlling the balance of effector versus memory fates in human T cells.
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