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  • The American Association of Immunologists  (3)
  • 1
    Online Resource
    Online Resource
    Cytotoxic T Cell Functions Accumulate When CD4 Is Downregulated by CD4+ T Cells in African Green Monkeys
    The American Association of Immunologists ; 2017
    In:  The Journal of Immunology Vol. 198, No. 11 ( 2017-06-01), p. 4403-4412
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 198, No. 11 ( 2017-06-01), p. 4403-4412
    Abstract: African green monkeys (AGMs) are a natural host of SIV that do not develop simian AIDS. Adult AGMs naturally have low numbers of CD4+ T cells and a large population of MHC class II–restricted CD8αα T cells that are generated through CD4 downregulation in CD4+ T cells. In this article, we study the functional profiles and SIV infection status in vivo of CD4+ T cells, CD8αα T cells, and CD8αβ T cells in lymph nodes, peripheral blood, and bronchoalveolar lavage fluid of AGMs and rhesus macaques (in which CD4 downregulation is not observed). We show that, although CD8αα T cells in AGMs maintain functions associated with CD4+ T cells (including Th follicular functionality in lymphoid tissues and Th2 responses in bronchoalveolar lavage fluid), they also accumulate functions normally attributed to canonical CD8+ T cells. These hyperfunctional CD8αα T cells are found to circulate peripherally, as well as reside within the lymphoid tissue. Due to their unique combination of CD4 and CD8 T cell effector functions, these CD4− CD8αα T cells are likely able to serve as an immunophenotype capable of Th1, follicular Th, and CTL functionalities, yet they are unable to be infected by SIV. These data demonstrate the ambiguity of CD4/CD8 expression in dictating the functional capacities of T cells and suggest that accumulation of hyperfunctional CD8αα T cells in AGMs may lead to tissue-specific antiviral immune responses in lymphoid follicles that limit SIV replication in this particular anatomical niche.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1700136
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2017
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Unique regulation of the DNA methylation machinery in natural hosts contributes to CD4 gene repression and SIV disease non-progression
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 248.7-248.7
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 248.7-248.7
    Abstract: African green monkeys (AGMs) are natural hosts of Simian immunodeficiency virus (SIV) that post-thymically downregulate CD4 to maintain a large population of CD4−CD8aa+ virus-resistant T cells which retain T-helper functionality. AGMs can become aviremic and apparently cured of SIV by down-regulating CD4 to completion. To understand the mechanisms of this process, purified CD4+ T cells from four AGMs, closely-related Patas monkeys, and rhesus macaques were stimulated with SEB for 5 days and RNAseq was performed on divided cells induced to downregulate CD4 (AGM, Patas) and those that maintain CD4 expression (rhesus). 1,917 DEGs were revealed to be common among divided, CD4-downregulated AGM and Patas T cells, yet unique from divided rhesus CD4+ T cells. Genes well-known to be regulated in natural hosts were selectively present in this dataset, including CD4, CD8A, and CXCR6 (p= 1.27e−27, 2.68e−5, 6.72e−15, respectively). Pathway analysis of DEGs revealed proteins involved in DNA methylation to be enriched in CD4-downregulated AGM and Patas T cells (p=0.013). Inhibition of DNA methyltransferases (DNMT) with 5-aza-2 deoxycitidine inhibited CD4 downregulation in AGM CD4+ T cells induced to divide in vitro (p=0.005), indicating CD4 can be pharmacologically manipulated in natural hosts. Cytosine residues within the AGM CD4 promoter region became methylated during CD4 downregulation in vitro (p= & lt; 0.0001), and were stably inherited in AGM CD4−CD8aa+ T cells sorted directly ex vivo. These results suggest AGMs employ epigenetic mechanisms to durably silence the CD4 gene. Manipulation of these mechanisms could provide avenues for modulating SIV/HIV-1 entry receptor expression in hosts that become progressively HIV-1/SIV-infected.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.248.7
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Epigenetic Reprogramming Leads to Downregulation of CD4 and Functional Changes in African Green Monkey Memory CD4+ T Cells
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 209, No. 2 ( 2022-07-15), p. 337-345
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 209, No. 2 ( 2022-07-15), p. 337-345
    Abstract: African green monkeys (AGMs), Chlorocebus pygerythrus, are a natural host for a lentivirus related to HIV, SIV. SIV-infected AGMs rarely progress to AIDS despite robust viral replication. Though multiple mechanisms are involved, a primary component is the animals’ ability to downregulate CD4 expression on mature CD4+ Th cells, rendering these cells resistant to infection by SIV. These CD8αα+ T cells retain functional characteristics of CD4+ Th cells while simultaneously acquiring abilities of cytotoxic CD8αβ+ T cells. To determine mechanisms underlying functional differences between T cell subsets in AGMs, chromatin accessibility in purified populations was determined by assay for transposase-accessible chromatin sequencing. Differences in chromatin accessibility alone were sufficient to cluster cells by subtype, and accessibility at the CD4 locus reflected changes in CD4 expression. DNA methylation at the CD4 locus also correlated with inaccessible chromatin. By associating accessible regions with nearby genes, gene expression was found to correlate with accessibility changes. T cell and immune system activation pathways were identified when comparing regions that changed accessibility from CD4+ T cells to CD8αα+ T cells. Different transcription factor binding sites are revealed as chromatin accessibility changes, and these differences may elicit downstream changes in differentiation. This comprehensive description of the epigenetic landscape of AGM T cells identified genes and pathways that could have translational value in therapeutic approaches recapitulating the protective effects CD4 downregulation.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200109
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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