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  • 1
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 194, No. 1_Supplement ( 2015-05-01), p. 198.5-198.5
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 1_Supplement ( 2015-05-01), p. 198.5-198.5
    Abstract: The molecular mechanisms that underpin acquisition and maintenance of lineage specific gene expression by virus-specific CD8+ T cells are not fully delineated. Post-translational modifications (PTMs) of genome associated histone proteins are a key mechanism for regulating gene expression. We mapped genome wide changes in histone PTM deposition during virus-specific CD8+ T cell differentiation. By comparing the location and level of deposition of a combination of H3K4me1, H3K4me2, H3K4me3, H3K27me3, H3K27Ac, chromatin accessibility and binding of the histone acetyltransferase, p300, we could map both known and putative enhancer elements that are differentially regulated between naive, effector and memory virus-specific CD8+ T cells. Using this epigenetic blueprint, we identified putative transcriptional enhancers located upstream of the Ccl5 gene, a key CD8+ T cell effector gene. We demonstrate that acquisition of Ccl5 transcription upon T cell activation is regulated via temporal and transcription factor (TF) dependent chromatin remodelling. Using chromatin conformation capture (3C) to measure enhancer-promoter interactions, we show that that TF dependent looping of these enhancer elements onto the Ccl5 promoter correlated with transcriptional activation and potential. These studies form a platform for more in depth analysis of key non-coding regulatory elements that regulate acquisition of virus-specific T cell gene expression and maintenance into memory.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    The American Association of Immunologists ; 2016
    In:  The Journal of Immunology Vol. 196, No. 1_Supplement ( 2016-05-01), p. 129.2-129.2
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 196, No. 1_Supplement ( 2016-05-01), p. 129.2-129.2
    Abstract: A long-lived pool of potent memory cells is the defining feature of adaptive immunity. Memory CD8 T cells offer protection for the life of the host due to their unique capabilities to survive in the absence of antigen and respond rapidly to secondary challenge. Therefore, effective CD8 T cell memory is the goal of cell-mediated vaccination strategies. While it is well established that CD4 help is required for CD8 T cell memory formation, it is unclear when during CD8 differentiation this help is required. Further, the affect that CD4 help has on the transcriptional profiles of CD8 T cells and the molecular pathways they use during the generation and maintenance of memory CD8 T cells remains elusive. Using a mouse model of Influenza A virus infection, where priming occurs in the presence or absence of CD4 T cell help, we have pinpointed that help is required during the initial priming of CD8 T cells, and not during memory maintenance or recall. Genome wide RNA-sequencing analysis of the transcriptional signatures between resting “helped” and “ unhelped” memory CD8 T cells reveals surprisingly few differentially expressed genes. However, upon reactivation, “helped” memory CD8 T cells exhibited greater transcriptional up regulation than their “unhelped” counterparts, and utilization of alternate molecular pathways. Our analysis revealed that CD4 help during initial priming is essential for establishing a memory cell pool with enhanced transcriptional potential. Intriguing metabolism differences are currently being further dissected based on this RNA-sequencing data. Thus, CD4 T cell dependent programming likely underpins rapid responsiveness, a key characteristic of memory CD8 T cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2016
    detail.hit.zdb_id: 1475085-5
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  • 3
    In: Journal of Experimental Medicine, Rockefeller University Press, Vol. 218, No. 6 ( 2021-06-07)
    Abstract: Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1− memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede TRM cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1− cells restored TRM generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream TRM cell differentiation. Importantly, Ptpn2-deficient TRM cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal TRM cell formation in skin and reveal an important role of Ptpn2 in regulating TRM cell functionality.
    Type of Medium: Online Resource
    ISSN: 0022-1007 , 1540-9538
    RVK:
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2021
    detail.hit.zdb_id: 1477240-1
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