Constitutive CD8 expression drives innate CD8+ T cell differentiation via induction of iNKT2 subset
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ABSTRACT:
PROVIDER: PRJNA545741 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9172308.fastq.gz | Fastqsanger.gz | |||
| SRR9172309.fastq.gz | Fastqsanger.gz |
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Project description:Constitutive CD8 expression drives innate CD8+ T cell differentiation via induction of iNKT2 subset.
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Project description:Temporal down-regulation of the CD8 co-receptor after receiving positive-selection signals has been proposed to serve as an important determinant to segregate helper versus cytotoxic lineages by generating differences in the duration of TCR signaling between MHC-I and MHC-II selected thymocytes. By contrast, little is known about whether CD8 also modulates TCR signaling engaged by the non-classical MHC-I-like molecule, CD1d, during development of invariant natural killer T (iNKT) cells. Here, we show that constitutive transgenic CD8 expression resulted in enhanced differentiation of innate memory-like CD8+ thymocytes in both a cell-intrinsic and cell-extrinsic manner, the latter being accomplished by an increase in the IL-4-producing iNKT2 subset. Skewed iNKT2 differentiation requires cysteine residues in the intracellular domain of CD8α that are essential for transmitting cellular signaling. Collectively, these findings shed a new light on the relevance of CD8 down-regulation in shaping the balance of iNKT-cell subsets by modulating TCR signaling.
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Project description:Innate memory phenotype (IMP) CD8+ T cells are non-conventional αβ T cells exhibiting features of innate immune cells, and are significantly increased in the absence of non-receptor tyrosine kinase ITK. Their developmental path and function are not clear, particularly whether they can contribute to antigen specific responses. We found that WT bone marrow gives rise to IMP CD8+ T cells in irradiated MHCI-/- recipients, resembling those in Itk-/- mice determined by expression of surface markers. However, CD8+ T cells share similar expression of memory markers. We used microarrays to compare the global programme of gene expression to determine whether the CD8+ T cells selected by hematopoietic MHCI are IMP CD8+ T cells as observed in the absence of ITK, or the result of homeostatic expansion of T cell contamination in the donor bone marrow. Through analysis of global gene expression correlation and differential expression, we determined that hematopoietic MHCI dependent IMP CD8+ T cells generated in irradiated MHCI-/- recipients, resemble those in Itk-/- mice, but distinct from CD8+ T cells derived via homeostatic proliferation. Cell sorting was performed using a FACSAria Cell Sorter (BD Biosciences, San Diego, CA). IMP CD8+ T cells (TCRβ+CD8α+CD44hi) were sorted from splenocytes of WT→MHCI-/- chimeras 8 weeks post transplantation and 8-week old Itk-/- mice. To generate HP cells, naïve CD8+ T cells (TCRβ+CD8α+CD44lo) were sorted and injected into Rag1-/- recipients (0.5 million /mouse, retro-orbital injection), followed by sorting of TCRβ+CD8α+ splenocytes 8 weeks post adoptive transfer. We sought to compare cells with the same gender and age, thus all donors were female, and ages (absolute age for Itk null and age post transfer for chimeras and HP model) were 8 weeks.
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Project description:CD8 Tissue Resident Memory (TRM) induction
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Project description:Virtual memory T (TVM) cells are a T-cell subtype that exhibit a memory phenotype without prior exposure to a foreign antigen. Although several recent studies suggest that TVM cells exert anti-viral and anti-bacterial function, pathological roles of TVM cells causing inflammatory diseases have not been studied. Here, we identified a novel CD8+ T-cell subset (CD44s-hiCD49dlo CD8+ T cells), which is originated from TVM cells and can cause a chronic inflammatory disease, alopecia areata (AA). In the skin of alopecic mice, we detected a distinct TVM-cell subpopulation characterized by superior expression of CD44 and features of tissue residency, which was transcriptionally, phenotypically, and functionally distinct from conventional CD8+ TVM cells. Mechanistically, this cell population could be induced from conventional TVM cells by IL-12, IL-15, and IL-18 stimulation. Moreover, the pathological activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-depedent innate-like cytotoxicity against target cells, which was further augmented by IL-15 stimulation and triggered the onset of disease. Collectively, our results suggest a new immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.
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Project description:Virtual memory T (TVM) cells are a T-cell subtype that exhibit a memory phenotype without prior exposure to a foreign antigen. Although several recent studies suggest that TVM cells exert anti-viral and anti-bacterial function, pathological roles of TVM cells causing inflammatory diseases have not been studied. Here, we identified a novel CD8+ T-cell subset (CD44s-hiCD49dlo CD8+ T cells), which is originated from TVM cells and can cause a chronic inflammatory disease, alopecia areata (AA). In the skin of alopecic mice, we detected a distinct TVM-cell subpopulation characterized by superior expression of CD44 and features of tissue residency, which was transcriptionally, phenotypically, and functionally distinct from conventional CD8+ TVM cells. Mechanistically, this cell population could be induced from conventional TVM cells by IL-12, IL-15, and IL-18 stimulation. Moreover, the pathological activity of CD44s-hiCD49dlo CD8+ T cells was mediated by NKG2D-depedent innate-like cytotoxicity against target cells, which was further augmented by IL-15 stimulation and triggered the onset of disease. Collectively, our results suggest a new immunological mechanism through which TVM cells can cause chronic inflammatory disease by innate-like cytotoxicity.
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Project description:This SuperSeries is composed of the following subset Series: GSE22768: Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vivo analysis GSE22769: Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vitro analysis To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity. Refer to individual Series
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2011-01-08 | E-GEOD-26491 | biostudies-arrayexpress
Project description:To understand better the nature of the poor response of human neonates to intracellular pathogens, we evaluated the transcriptome of neonates as compared to adult naïve CD8-T cells. A specific transcription signature of the neonatal cells was found, characterized by a lower expression of signalling and CTL functional genes and a high expression of maturation, cell cycle and innate-immunity associated genes. Functional assays demonstrated that neonatal CD8-T cells undergo homeostatic proliferation, transcribe antimicrobial peptides and produce reactive oxygen species. Master transcription factors were found presumably responsible for this specific signature. Genome wide epigenetic studies showed a corresponding chromatin signature for a number of the differentially expressed genes. Altogether our results show that CD8 neonatal T cells have a particular genetic program with functions within the innate immune response, while still undergoing their maturation process. Neonates are highly susceptible to infections by intracellular pathogens, which are a major cause of infant morbidity and mortality. CD8-T cells control intracellular pathogens through cytotoxic mechanisms in an antigen-dependent manner. We found that human neonatal CD8-T cells, as compared to adult lymphocytes, had a distinctive pattern of gene transcription, characterized by the lower expression of genes involved in TCR signalling and cytotoxicity and a high expression of genes involved in cell cycle and innate immunity. Functional studies corroborated that neonatal CD8-T cells are less cytotoxic, transcribe antimicrobial peptides and produce reactive oxygen species. These properties could explain the high sensitivity of neonates to intracellular pathogen infections and outline novel functions of neonatal CD8-T cells. PBMC total RNAs from Adult and Neonate subjects were profiled after hybridization with Agilent SurePrint G3 Human GE 8x60K Microarray. CD8-T cells mRNA were extracted from 8 samples including: 4 Adults and 4 Neonates.
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