The transcription factor AFF3 is necessary to maintain metabolic quiescence in naïve CD8 T cells and prevent premature immune aging
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE331107 | GEO | 2026/06/01
REPOSITORIES: GEO
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Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).
2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress
Project description:The transcription factor AFF3 is necessary to maintain metabolic quiescence in naïve CD8 T cells and prevent premature immune aging
| PRJNA1466903 | ENA
Project description:Fission yeast Schizosaccharomyces pombe is a model for studying cellular quiescence. Shifting to medium without a nitrogen-source induces proliferative cells to enter long-term G0 quiescence. Klf1 is a Kruppel-like transcription factor with a 7-amino acid-spaced C2H2-type zinc finger motif. The deletion mutant M-bM-^HM-^Fklf1 normally divides in vegetative medium, but proliferation is not restored after long-term G0 quiescence. Cell biologic, transcriptomic, and metabolomic analyses revealed a unique phenotype of the M-bM-^HM-^Fklf1 mutant in quiescence. Mutant cells had diminished transcripts related to signaling molecules for switching to differentiation. In contrast, proliferative metabolites for cell-wall assembly and antioxidants significantly increased. Further, the size of the M-bM-^HM-^Fklf1 cells is markedly increased during quiescence due to the aberrant accumulation of calcofluor-positive chitin-like materials beneath the cell wall. After 4 weeks quiescence, the ability for reversible proliferation is lost, but energy metabolism is maintained. Klf1 thus plays a role in G0 phase longevity through enhancing the differentiation signal and suppressing metabolism for growth. If Klf1 is lost, S. pombe fails to maintain a constant cell size during quiescence. Gene expression profile of fission yeast wild type cells and klf1-gene disruptant cells in proliferating state and in quiescent state. Type of experiment: Comparing between wild type cells and klf1-gene disruptant cells in proliferating condition and in quiescent condition. Experimental factor: Exponentially proliferating state in synthetic medium, EMM2, and quiescent G0 state in nitrogen-depleted synthetic medium, EMM2-N. Quality control steps taken: All experiments were repeated twice in each condition.
2013-12-01 | E-GEOD-50986 | biostudies-arrayexpress
Project description:Naïve T cells maintain quiescence yet must respond rapidly to antigens, but how they prime this capacity is unclear. We identify histone variant H2A.Z as a key regulator of an epigenetic training program that licenses quiescent naïve CD8+ T cells for future activation. H2A.Z deficiency disrupts naïve T cell homeostasis and effector responses. Multi-omics reveals that H2A.Z is selectively deposited at OXPHOS gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic IL-7 signaling and regulated by transcription factor GABPα. Age-related decline in IL-7 signaling reduces H2A.Z occupancy and impairs T cell activation, while IL-7 supplementation or enforced H2A.Z expression rescues this defect. H2A.Z overexpression also enhances CAR-T cell stemness and antitumor efficacy. Our work defines an IL-7R–GABPα–H2A.Z–OXPHOS axis that epigenetically establishes metabolic and functional fitness in quiescent T cells, offering insights for immunotherapy targeting ageing and tumors.
2026-08-10 | GSE306052 | GEO
Project description:Naïve T cells maintain quiescence yet must respond rapidly to antigens, but how they prime this capacity is unclear. We identify histone variant H2A.Z as a key regulator of an epigenetic training program that licenses quiescent naïve CD8+ T cells for future activation. H2A.Z deficiency disrupts naïve T cell homeostasis and effector responses. Multi-omics reveals that H2A.Z is selectively deposited at OXPHOS gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic IL-7 signaling and regulated by transcription factor GABPα. Age-related decline in IL-7 signaling reduces H2A.Z occupancy and impairs T cell activation, while IL-7 supplementation or enforced H2A.Z expression rescues this defect. H2A.Z overexpression also enhances CAR-T cell stemness and antitumor efficacy. Our work defines an IL-7R–GABPα–H2A.Z–OXPHOS axis that epigenetically establishes metabolic and functional fitness in quiescent T cells, offering insights for immunotherapy targeting ageing and tumors.
2026-08-10 | GSE305926 | GEO
Project description:Naïve T cells maintain quiescence yet must respond rapidly to antigens, but how they prime this capacity is unclear. We identify histone variant H2A.Z as a key regulator of an epigenetic training program that licenses quiescent naïve CD8+ T cells for future activation. H2A.Z deficiency disrupts naïve T cell homeostasis and effector responses. Multi-omics reveals that H2A.Z is selectively deposited at OXPHOS gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic IL-7 signaling and regulated by transcription factor GABPα. Age-related decline in IL-7 signaling reduces H2A.Z occupancy and impairs T cell activation, while IL-7 supplementation or enforced H2A.Z expression rescues this defect. H2A.Z overexpression also enhances CAR-T cell stemness and antitumor efficacy. Our work defines an IL-7R–GABPα–H2A.Z–OXPHOS axis that epigenetically establishes metabolic and functional fitness in quiescent T cells, offering insights for immunotherapy targeting ageing and tumors.
2026-08-10 | GSE305895 | GEO
Project description:Naïve T cells maintain quiescence yet must respond rapidly to antigens, but how they prime this capacity is unclear. We identify histone variant H2A.Z as a key regulator of an epigenetic training program that licenses quiescent naïve CD8+ T cells for future activation. H2A.Z deficiency disrupts naïve T cell homeostasis and effector responses. Multi-omics reveals that H2A.Z is selectively deposited at OXPHOS gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic IL-7 signaling and regulated by transcription factor GABPα. Age-related decline in IL-7 signaling reduces H2A.Z occupancy and impairs T cell activation, while IL-7 supplementation or enforced H2A.Z expression rescues this defect. H2A.Z overexpression also enhances CAR-T cell stemness and antitumor efficacy. Our work defines an IL-7R–GABPα–H2A.Z–OXPHOS axis that epigenetically establishes metabolic and functional fitness in quiescent T cells, offering insights for immunotherapy targeting ageing and tumors.
2026-08-10 | GSE305868 | GEO
Project description:The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is however not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly upregulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Lastly, we found that a gene expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging.
2019-10-11 | GSE124109 | GEO
Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.
2015-06-16 | E-GEOD-67593 | biostudies-arrayexpress
Project description:Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a “backwards” flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole. mRNAs were analyzed by two color microarray from two separate human neonatal dermal fibroblasts cell lines in proliferating, 7 days contact inhibition, or 14 days contact inhibition. Contact inhibited samples were co-hybridized to proliferating samples as a control, while an additional array co-hybridized the two proliferating samples to analyze reproducibility.
2012-11-30 | E-GEOD-42612 | biostudies-arrayexpress