ATAC seq of CD8 TILs of WT and Card11 mutant mice(K215M)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE292541 | GEO | 2025/04/23
REPOSITORIES: GEO
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Project description:To investigate the impact of Card11 on TIL differentiation, we isolated TILs from B16-F10 tumors of WT mice, E134G mice, and K215M mice and performed scRNA seq. We also sorted tumor-infiltrating lymphocytes (TILs) from melanoma(B16-F10) of WT mice and conducted scRNA and scTCR sequencing. To further investigate the impact of Card11 on TCR clonal diversity, we sorted CD8 T cells from melanoma WT mice or K215M mice and performed scRNA and scTCR sequencing.
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Project description:To investigate the impact of Card11 on TCR downstream signaling, we isolated naive CD8+ T cells from wild-type (WT) mice and Card11 mutant mice (K215M and E134G). These cells were stimulated in vitro with anti-CD3/CD28 for 24 hours, after which RNA was extracted from the stimulated cells for sequencing analysis.
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Project description:Antigen receptor signaling pathways that control lymphocyte activation depend upon signaling hubs and negative regulatory proteins to fine-tune signaling output to ensure host defense and avoid potentially pathogenic hyperresponses. CARD11 is a critical signaling scaffold that translates T Cell Receptor triggering into the activation of branching NF-kB, JNK, mTOR and Akt pathways. Here we identify QRICH1 as a regulator of CARD11 signaling that mediates a previously undiscovered intracellular checkpoint for CD8+ T cell activation. QRICH1 inducibly associates with CARD11 following TCR engagement and negatively regulates CARD11 signaling to the IKK complex and NF-kB. QRICH1 binding to CARD11 occurs after TCR-induced CARD11 opening and is controlled by an autoregulatory intramolecular interaction between QRICH1 protein domains of previously uncharacterized function. Using mice deficient in QRICH1 in the T cell lineage, we show that QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8+ T cells by regulating numerous gene targets critical for CD8+ T cell function. Our results define a previously unappreciated component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.
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Project description:Immune checkpoint inhibitor (ICI) therapies revitalize anti-cancer responses by intercepting protein-protein interactions between exhausted CD8 T (Tex) cells and cancer cells (e.g. PD-1:PD-L1). However, up to 50% of patients receiving ICIs relapse, warranting further interrogation of the underpinnings of Tex. We conducted RNA-seq meta-analysis of Tex versus effector (Teff) mouse CD8 T cells, and highlighted NRF2 transcriptional targets as the most upregulated gene set in Tex cells. LCMV or cancer inoculation of mice bearing NRF2 hyperactive—or Keap1-/- (NRF2 negative regulator)—T cells demonstrated that NRF2 drives Tex; evidenced by increased co-inhibitory marker (PD-1/TIM-3) expression and reduced cytokine (IFN-g/Granzyme-B) production. RNA-seq of Keap1-/- highlight Ptgir—which encodes the prostacyclin lipid receptor— as the most upregulated gene versus WT T cells. Accordingly, PTGIR knockout in NRF2-hyperactive/ Tex cells decreased PD-1/TIM-3 expression, increased cytokine production, and attenuated tumor growth. Our data underscore PTGIR as a NRF2-regulated Tex driver and illuminate an unconventional immune checkpoint class potentially based on protein-lipid interactions
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Project description:In order to investigate the molecular mechanism of CARD11 in immune cell system, we applied the RNA-seq analysis using RNA isolated from WT and CARD11 mutant (E134G and K215M) mouse spleen B cells. By comparing the transcriptome files, we found some different expressed gene involved in due to the CARD11 point mutation and in vitro RT-PCR had confirmed this result.
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Project description:Several “primary atopic disorders” are linked to monogenic defects that attenuate TCR signaling, favoring T helper 2 (TH2) cell differentiation. Patients with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease suffer from severe atopy, caused by germline loss-of-function/dominant interfering (LOF/DI) CARD11 variants. The CARD11 scaffold enables TCR-induced activation of NF-κB, mTORC1, and JNK signaling, yet the function of CARD11-dependent JNK signaling in T cells remains nebulous. Here we show that CARD11 is critical for TCR-induced activation of JNK1 and JNK2, as well as canonical JUN/FOS AP-1 family members. Patient-derived CARD11 DI variants attenuated wild-type CARD11 JNK signaling, mirroring effects on NF-κB. Transcriptome profiling revealed JNK inhibition upregulated TCR-induced expression of GATA3 and NFATC1, key transcription factors for TH2 cell development. Further, impaired CARD11-JNK signaling was linked to enhanced GATA3 expression in CADINS patient T cells. Our findings reveal a novel intrinsic mechanism connecting impaired CARD11-dependent JNK signaling to enhanced GATA3/NFAT2 induction and TH2 cell differentiation in CADINS patients.
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Project description:T cell exhaustion is a state of functional decline in T cells, driven by chronic antigen exposure and inhibitory signals within the tumor microenvironment. Exhausted CD8+ T cells (Tex) derive from precursor exhausted T cells (Tpex), a self-renewing population responsible for the proliferative burst observed in anti-PD-1 therapies. Exhausted cells are exposed to adenosine in the tumor, yet the role of the CD73/adenosine axis and Tpex/Tex differentiation remains unclear. Using an in vitro model for CD8+ T cell exhaustion, we found that CD73 expression increased during Tpex formation and that its expression is negatively correlated with Tex generation. CD73-deficient (CD73KO) CD8⁺ T cells showed impaired activation and reduced progression to Tex. Moreover, we demonstrated that CD73 promotes transcriptional expression of the adenosine receptor A2A (A2AR) and the differentiation into IFNγ/TNFα-producing Tex cells. RNAseq analysis of exhausted CD73KO CD8+ T cells showed a more stem-like transcriptomic profile and enrichment in genes associated with the immune response than their WT counterpart. In vivo, co-transfer of naïve CD73 KO and WT tumor antigen-specific CD8⁺ T cells into tumor-bearing mice showed increased Tpex frequency and numbers among CD73KO cells in tumors. Conversely, in vitro exhaustion in the presence of A2AR agonists decreased Tex frequency and activation/exhaustion markers, while increasing CD73 and CD62L, markers associated with stemness. Supporting this, A2AR blockade with SYN115 in tumor-bearing mice reduced Tpex markers and increased Tex differentiation. Altogether, our data suggest CD73 promotes Tpex-to-Tex differentiation, whereas adenosine-A2AR signaling supports Tpex maintenance in the tumor microenvironment.
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