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QRICH1 Mediates an Intracellular Checkpoint for CD8+ T Cell Activation via the CARD11 Signalosome

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE280713 | GEO | 2025/01/28

REPOSITORIES: GEO

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Project description:Activation of peripheral T lymphocytes in the absence of pathogen induced inflammation or costimulatory signals results in tolerance. Two different tolerance mechanisms have been described, deletion and anergy. We recently demonstrated that an important variable which is responsible for the decision between anergy and deletion for CD8 T cells is the strength of signaling through the T cell receptor(Redmond and Sherman, Immunity 22:275,2005). However, it is not know what the downstream signals are that result in death(deletion) vs. survival(anergy)of the activated cells. Marth and co-workers have previously shown that CD8 T cell apoptosis under conditions similar to those that occur during tolerance in vivo may involve a change in protein glycosylation (Van Dyken et.al., Mol.Cell.Bio.27:1096,2007).In order to assess the role of protein glycosylation in the decision between deletion vs.anergy in immune tolerance, we have prepared purified TCR transgenic CD8 T cells stimulated in vivo using a strong antigenic signal (anergy conditions) or a weak antigenic signal (deletion conditions) with cognate antigen. We wish to assess transcriptional differences in genes involved in protein glycosylation in these 2 cell populations. The control population will be naive trangenic CD8 cells. Dr. Sherman's lab aims to assess the role of protein glycosylation in the decision between deletion vs. anergy in immune tolerance, they have prepared purified TCR transgenic CD8 T cells stimulated in vivo using a strong antigenic signal (anergy conditions) or a weak antigenic signal (deletion conditions) with cognate antigen. Dr. Sherman's lab wishes to assess transcriptional differences in genes involved in protein glycosylation in these 2 cell populations. Then control population will be naïve transgenic CD8 cells. RNA preparations of mouse CD8 T cells from the B10D2 strain with three different conditions (Naïve, Deleted, and Anergic) were sent to the Microarray Core (E). The RNA was amplified, labeled, and hybridized to both the GLYCOv3 and Mouse 430A_2.0 microarrays.

Project description:Activation of peripheral T lymphocytes in the absence of pathogen induced inflammation or costimulatory signals results in tolerance. Two different tolerance mechanisms have been described, deletion and anergy. We recently demonstrated that an important variable which is responsible for the decision between anergy and deletion for CD8 T cells is the strength of signaling through the T cell receptor(Redmond and Sherman, Immunity 22:275,2005). However, it is not know what the downstream signals are that result in death(deletion) vs. survival(anergy)of the activated cells. Marth and co-workers have previously shown that CD8 T cell apoptosis under conditions similar to those that occur during tolerance in vivo may involve a change in protein glycosylation (Van Dyken et.al., Mol.Cell.Bio.27:1096,2007).In order to assess the role of protein glycosylation in the decision between deletion vs. anergy in immune tolerance, we have prepared purified TCR transgenic CD8 T cells stimulated in vivo using a strong antigenic signal (anergy conditions) or a weak antigenic signal (deletion conditions) with cognate antigen. We wish to assess transcriptional differences in genes involved in protein glycosylation in these 2 cell populations. The control population will be naive trangenic CD8 cells. Dr. Sherman's lab aims to assess the role of protein glycosylation in the decision between deletion vs. anergy in immune tolerance, they have prepared purified TCR transgenic CD8 T cells stimulated in vivo using a strong antigenic signal (anergy conditions) or a weak antigenic signal (deletion conditions) with cognate antigen. Dr. Sherman's lab wishes to assess transcriptional differences in genes involved in protein glycosylation in these 2 cell populations. Then control population will be naïve transgenic CD8 cells. RNA preparations of mouse CD8 T cells from the B10D2 strain with three different conditions (Naïve, Deleted, and Anergic) were sent to the Microarray Core (E). The RNA was amplified, labeled, and hybridized to the GLYCOv4 microarrays.

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QRICH1 Mediates an Intracellular Checkpoint for CD8+ T Cell Activation via the CARD11 Signalosome

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