Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2

Pękalski, Marcin Ł.; Garćıa, Arcadio Rubio; Ferreira, Ricardo C.; Rainbow, Daniel B.; Smyth, Deborah J.; Mashar, Meghavi; Brady, Jane; Savinykh, Natalia; Dopico, Xaquín Castro; Mahmood, Sumiyya; Duley, Simon; Stevens, Helen; Walker, Neil; Cutler, Antony J.; Waldron‐Lynch, Frank; Dunger, David B.; Shannon-Lowe, Claire; Coles, Alasdair; Jones, Joanne L.; Wallace, Chris; Todd, John A.; Wicker, Linda S.

doi:10.1172/jci.insight.93739

Cited by 56 publications

(54 citation statements)

References 52 publications

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“…Cytokine‐driven differentiation is a hallmark of virtual memory CD8 cells that accumulate in the mouse with age (Nikolich‐Zugich, ). Naïve human T cells exhibit phenotypic changes that are suggestive for partial activation or differentiation (den Braber et al, ; Kohler & Thiel, ; Pekalski et al, ). Also, alterations in microRNA expression patterns with aging are indicative of T‐cell differentiation, including the loss of miR‐181a (Gustafson et al, ; Li et al, ) and an increase in miR‐21 that favors the activation of TF networks characterized by the reduction in TCF7, BCL6, and ID3 (Kim et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…A similar but less pronounced trend is seen for naïve CD4 T cells (Goronzy, Hu, Kim, Jadhav, & Weyand, ). T‐cell phenotypic changes indicating an altered composition with age include the loss of CD31, CR1, and CR2 and the gain of CD25 in subsets of naïve CD4 T cells (den Braber et al, ; Kohler & Thiel, ; Pekalski et al, ). Moreover, TCR activation thresholds and signaling pathways that control differentiation processes change in an age‐dependent pattern.…”

Section: Introductionmentioning

confidence: 99%

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Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Li²,

Ye³

et al. 2019

Aging Cell

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With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T‐cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T‐cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging‐associated changes in the transcription factor profile favor TH9 commitment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Li²,

Ye³

et al. 2019

Aging Cell

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“…RTEs continue their post‐thymic maturation for approximately 3 weeks, during which they exhibit distinct functions and chromatin architecture from those mature naïve T cells, which have circulated longer . Newly egressed human RTEs express CR1 and CR2 and produce IL‐8 following activation and can be used to distinguish those RTEs that have undergone increased rounds of peripheral division . Activated CD8 + RTEs have reduced effector functions such as proliferation, IFNγ production, and IL‐2 production compared to mature naïve CD8 + T cells .…”

Section: Neonatal T‐cell Ontogenymentioning

confidence: 99%

“…14 Newly egressed human RTEs express CR1 and CR2 and produce IL-8 following activation and can be used to distinguish those RTEs that have undergone increased rounds of peripheral division. 15 Activated CD8 + RTEs have reduced effector functions such as proliferation, IFN production, and IL-2 production compared to mature naïve CD8 + T cells. 12,13,16,17 Stimulation of human RTEs, similar to mice, results in decreased production of IL-2, IL-4, and IFN compared to mature naïve T cells.…”

Section: Neonatal T-cell Ontogenymentioning

confidence: 99%

Dissecting the defects in the neonatal CD8+ T-cell response

Fike

Kumova

Carey

2019

Journal of Leukocyte Biology

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The neonatal period presents a complex scenario where the threshold of reactivity toward colonizing microbiota, maternal antigens, autoantigens, and pathogens must be carefully moderated and balanced. CD8+ T cells are critical for the response against intracellular bacteria and viruses, but this immune compartment maintains altered function relative to adult counterparts because of the unique challenges which infants face. Here, we review our current understanding of the factors which may promote the attenuation and altered function of the neonatal CD8+ T‐cell response and potential avenues for future study. Specifically, we have focused on the neonatal CD8+ T‐cell ontogeny, memory formation, TCR structure and repertoire, TCR inhibitory receptors, and the clinical implications of altered neonatal CD8+ T‐cell function. Special emphasis has been placed on examining the response of preterm neonates relative to term neonates and adults.

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“…Previously, transcriptome profiling using microarray of flow sorted cells from murine thymi has been reported, including for CD4 + and CD8 + T cells (13,14). So far, humans studies have explored the gene expression of recent thymic emigrants, immature T cell stages and naïve T cells, derived from peripheral blood (15,16) and umbilical cord blood (17). To our knowledge, no one has yet explored the human transcriptome of the finale stage of thymocytes, the SP T cells, or the transcriptome of the peripheral blood T cells in young children.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells

Helgeland

Gabrielsen

Akselsen

et al. 2019

Preprint

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Background: The thymus is a highly specialized organ of the immune system where T cell precursors develop and differentiate into self-tolerant CD4+ or CD8+ T cells. No studies to date have investigated how the human transcriptome profiles differ, between T cells still residing in the thymus and T cells in the periphery.Results: We have performed high-throughput RNA sequencing to characterize the transcriptomes of primary single positive (SP) CD4+ and CD8+ T cells from infant thymic tissue, as well as primary CD4+ and CD8+ T cells from infant and adult peripheral blood, to enable the comparisons across tissues and ages. In addition, we have assessed the expression of candidate genes related to autoimmune diseases in thymic CD4+ and CD8+ T cells. Thymic SP T cells displayed a broader transcriptome than peripheral T cells, indicated by a higher number of uniquely expressed genes. Comparing T cells of thymic and blood origin, revealed more differentially expressed genes, than between infant and adult blood. Functional enrichment analysis revealed an over-representation of genes involved in cell cycle and replication in thymic T cells, whereas infant blood T cells were dominated by immune related terms. Comparing adult and infant blood T cells, the former was enriched for inflammatory response, cytokine production and biological adhesion, while upregulated genes in infant blood T cells were associated with cell cycle, cell death and gene expression.Conclusion: This study provides valuable insight into the transcriptomes of the human primary SP T cells still residing within the thymus, and offers a unique comparison to the more frequently studied primary blood derived T cells. We discovered that genes involved in migration, homing and recirculation, between peripheral blood and lymphatic tissue, were particularly active in infant blood T cells, suggesting active migration and recirculation in young children.

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Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2

Cited by 56 publications

References 52 publications

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Dissecting the defects in the neonatal CD8+ T-cell response

Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells

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