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RNA-Seq of CD8+ T cells during LCMV infection [WT infection]

ABSTRACT: T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate.

ORGANISM(S): Mus musculus

PROVIDER: GSE111143 | GEO | 2018/04/19

REPOSITORIES: GEO

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ATAC-Seq of CD8+ T cells during activaion in vitro over the course 24 hours with and without Runx3

Project description:T cell receptor (TCR) stimulation of naïve CD8+ T cells initiates reprogramming of cis-regulatory landscapes that specify effector and memory cytotoxic T lymphocyte (CTL) differentiation. We mapped regions of hyper-accessible chromatin in naïve cells during TCR stimulation and discovered that the transcription factor (TF) Runx3 controls de novo access to memory CTL-specific cistromes prior to the first cell division, and is essential for memory CTL differentiation. Runx3 specifically promotes accessibility of cis-acting regions highly enriched with IRF, bZIP and Prdm1-like family TF motifs, upregulates IRF4 and establishes feed-forward transcriptional circuits that induce fundamental CTL attributes in memory precursor cells. Runx3 drives uncoupling from the naïve cell state, but subsequently restrains terminal differentiation of nascent CTL by preventing high expression of the TF T-bet and slowing effector cell proliferation. Enforced Runx3 expression enhances memory CTL differentiation and increases their numbers during iterative infections. Thus, Runx3 functions in a pioneering role to initialize and then ensure memory CTL differentiate.

2018-04-19 | GSE111144 | GEO

RNA-Seq of CD8+ T cells expressing different levels of Runx3 in during LCMV infection (in vivo)

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Runx3 pioneers chromatin accessibility of cis-regulatory landscapes that drive memory CTL formation

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Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using high-resolution mass spectrometry and RNAseq we systematically examine the impact of Pim1/Pim2 double deficiency on in vitro differentiated cytotoxic T lymphocytes (CTL) expanded in the cytokines IL-2 and IL-15 to generate effector or memory T cells respectively. We find that Pim kinases are dispensable for IL-15-driven memory cell differentiation, but that Pim1/2-deficiency has a selective impact on the transcriptome and proteome of IL-2 driven effector CD8 T cells. ~75% of Pim kinase-regulated proteins were not predicted by differences in mRNA in IL-2 expanded CTL. These included proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecules Granzyme A and B. We find that Pim kinases have this effect via control of protein translation. Another key finding was that the mRNA for key T cell homing receptors Ccr7, S1pr1 and CD62L was increased in Pim1/2-deficienct T cells and that this functionally enhancing homing to secondary lymphoid organs.

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Runx3 pioneers chromatin accessibility of cis-regulatory landscapes that drive memory CTL formation

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| PRJNA436011 | ENA

Doxycycline treated cytotoxic T lymphocytes

Project description:Recent work in immunometabolism has emphasised the role of mitochondria in both the innate and adaptive immune system. Mitochondria are important in T cell development and differentiation, but less is known about their role in CD8+ effector T cells (CTLs). We found that CTLs that lack the mitochondrial deubiquitinase USP30 undergo promiscuous mitophagy, destroying most of the cellular mitochondria. Surprisingly, this results in a markedly diminished killing capacity, while motility, signalling and secretion remain intact. This study uses quantitative DIA proteomics to measure the impact of USP30 deficiency on the global proteome of IL-2 maintained, 4.5 h TCR retriggered and 4.5 h TCR retriggered + cycloheximide CTL. We also measured the impact of pharmacologically inhibiting mitochondrial translation by performing Quantitative DIA proteomics on IL2 maintained or TCR retriggered CTL treated with the mitochondrial translation inhibitor doxycycline for 4.5 hrs. Unexpectedly, inhibition of mitochondrial translation, through genetic or pharmacologic methods, was the mechanism by which CTL killing was impaired. Reduced mitochondrial translation triggered attenuated cytosolic translation which precluded replenishment of secreted effector molecules thereby limiting the capacity of CTLs to serially kill multiple targets. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.

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