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Notch controls the magnitude of CD4+ T cell responses by promoting cellular longevity

ABSTRACT: Generation of effective immune responses requires expansion of rare antigen-specific CD4+ T cells. The magnitude of the response is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T cell responses is not fully clear. Here we describe a prominent role for the Notch pathway in this process. Co-activation of Notch allows accumulation of far greater numbers of activated CD4+ T cells than stimulation via T cell receptor and classical co-stimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4+ T cells. Instead, Notch protects activated CD4+ T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad anti-apoptotic gene expression program, which protects against intrinsic as well as extrinsic apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ are involved in this process. Correspondingly, CD4+ T cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings therefore show that Notch controls the magnitude of CD4+ T cell responses by promoting cellular longevity.

ORGANISM(S): Mus musculus

PROVIDER: GSE35547 | GEO | 2012/02/04

SECONDARY ACCESSION(S): PRJNA152281

REPOSITORIES: GEO

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Notch controls the magnitude of CD4+ T cell responses by promoting cellular longevity

Project description:Generation of effective immune responses requires expansion of rare antigen-specific CD4+ T cells. The magnitude of the response is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T cell responses is not fully clear. Here we describe a prominent role for the Notch pathway in this process. Co-activation of Notch allows accumulation of far greater numbers of activated CD4+ T cells than stimulation via T cell receptor and classical co-stimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4+ T cells. Instead, Notch protects activated CD4+ T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad anti-apoptotic gene expression program, which protects against intrinsic as well as extrinsic apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ are involved in this process. Correspondingly, CD4+ T cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings therefore show that Notch controls the magnitude of CD4+ T cell responses by promoting cellular longevity. Naïve CD4+ T cells were activated for 1 day (1 control sample and 1 experimental sample) or 3 days (3 control samples and 3 experimental samples) with antibodies to CD3 soluble and CD28 in the presence of recombinant Delta4-Ig (experimental samples) or control Ig (control samples).

2012-02-04 | E-GEOD-35547 | biostudies-arrayexpress

Mus musculus

Project description:Notch controls the magnitude of CD4+ T cell responses by promoting cellular longevity

| PRJNA152281 | ENA

Transmission of survival signals through Delta-like 1 on activated CD4+ T cells

Project description:Notch expressed on CD4+ T cells transduces signals that mediate their effector functions and survival by interacting with Notch ligands on adjacent cells. Although Notch signaling is known to be cis-inhibited by Notch ligands expressed on the same cells, the role of Notch ligands on T cells remain unclear. In this report we demonstrate that the Notch ligand Dll1 on CD4+ T cells transduces signals required for the maintenance of activated CD4+ T cells without affecting Notch signaling in the same cells. T cell-specific Dll1-deficient (Dll1-/-) mice did not show any defect in T cell development in thymus or spleen. Co-transfer of CD4+ T cells from Dll1-/- and control mice into recipient mice followed by immunization revealed a rapid decline of CD4+ T cells from Dll1-/- mice compared with control cells. Dll1-/- mice exhibited lower clinical scores of experimental autoimmune encephalitis than control mice. The expression of Notch target genes in CD4+ T cells from Dll1-/- mice was not affected, suggesting that Dll1 deficiency in T cells does not affect cis Notch signaling. Overexpression of the intracellular domain of Dll1 in Dll1-deficient CD4+ T cells partially rescued impaired survival. Our data highlight Dll1 as an independent regulator of Notch-signaling for the survival of activated CD4+ T cells, and provide new insight into the physiological roles of Notch ligands as well as a regulatory mechanism important for maintaining adaptive immune responses The mRNA expression in activated CD4+ T cells from mouse was obtained by DNA microarray analysis. These mRNA expression was compared.

2016-01-09 | E-GEOD-76693 | biostudies-arrayexpress

Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses - WT ILC2

Project description:Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens – including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals, but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 were found to be uniquely pre-primed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine producing capacity of ILC2. Moreover, amino acid determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.

2022-12-22 | PXD038792 | Pride

Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses - SLC7A5 and SLC7A8 KO

2022-12-22 | PXD038786 | Pride

Transmission of survival signals through Delta-like 1 on activated CD4+ T cells

2016-01-09 | GSE76693 | GEO

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [IN_VIVO_AW3]

Project description:Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22 (IL-22), IL-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.

2022-07-03 | GSE207312 | GEO

NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness [CULTURED_NCT07]

2022-07-03 | GSE207314 | GEO

Affinity and Dose of TCR Engagement Yield Proportional Enhancer and Gene Activity in CD4+ T Cells

Project description:Affinity and dose of T cell receptor (TCR) interaction with antigens govern the magnitude of CD4+ T cell responses, but questions remain regarding the quantitative translation of TCR engagement into downstream signals. We find that while the response of CD4+ T cells to antigenic stimulation is bimodal, activated cells exhibit analog responses proportional to signal strength. Gene expression output reflects TCR signal strength, providing a signature of T cell activation. Expression changes rely on a pre-established enhancer landscape and quantitative acetylation at AP-1 binding sites. Finally, we show that graded expression of activation genes depends on ERK pathway activation, suggesting that an ERK-AP-1 axis translates TCR signal strength into proportional activation of enhancers and genes essential for T cell function. CD4+ T cells from transgenic AND mice were sequenced under the conditions indicated. Replicates are included for each type of data (RNA-Seq, ChIP-Seq), and are numbered accordingly. The No Peptide condition serves as the untreated control for the peptide-treated samples, and inputs are provided for ChIP-Sequencing samples.

2016-06-01 | E-GEOD-69545 | biostudies-arrayexpress

Holo-TFIID controls the magnitude of a transcription burst and fine-tuning of transcription.

Project description:TFIID is a central player in activated transcription initiation. Recent evidence suggests that the role and composition of TFIID is more diverse than previously understood. To investigate the effects of changing the composition of TFIID in a simple system we depleted TAF1 from Drosophila cells and determined the consequences on metal induced transcription at an inducible gene, Metallothionein B (MtnB). We observe a marked increase in the levels of both the mature message and pre-mRNA in TAF1 depleted cells. Under conditions of continued metal exposure, we show that TAF1 depletion increases the magnitude of the initial transcription burst, but has no effect on the timing of that burst. We also show that TAF1 depletion causes delay in the shut-off of transcription upon removal of the stimulus. Thus TAFs are involved in both establishing an upper limit of transcription during induction and efficiently turning the gene off once the inducer is removed. Using genomewide nascent-seq we identify hundreds of genes that are controlled in a similar manner indicating that the findings at this inducible gene are likely generalizable to a large set of promoters. There is a long-standing appreciation for the importance of the spatial and temporal control of transcription. Here we uncover an important third dimension of control, the magnitude of the response. Our results show that the magnitude of the transcriptional response to the same signaling event, even at the same promoter, can vary greatly depending on the composition of the TFIID complex in the cell. Nascent RNA was sequenced from replicate samples of Drosophila S2 cells treated with double-stranded RNA directed against E. coli LacI (Control) or against Drosophlia TAF1 (experimental). Reads per kilo-base per million (RPKM) was determined for each gene and the control and experimental samples were compared to determine the genes that were affected by the depletion of TAF1.

2013-05-01 | E-GEOD-45873 | biostudies-arrayexpress

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