QRICH1 mediates an intracellular checkpoint for CD8+ T cell activation via the CARD11 signalosome

Sci Immunol. 2025 Mar 14;10(105):eadn8715. doi: 10.1126/sciimmunol.adn8715. Epub 2025 Mar 14.

Abstract

Antigen receptor signaling pathways that control lymphocyte activation depend on signaling hubs and negative regulatory proteins to fine-tune signaling outputs to ensure host defense and avoid pathogenic responses. Caspase recruitment domain-containing protein 11 (CARD11) is a critical signaling scaffold that translates T cell receptor (TCR) triggering into the activation of nuclear factor κB (NF-κB), c-Jun N-terminal kinase (JNK), mechanistic target of rapamycin (mTOR), and Akt. Here, we identify glutamine-rich protein 1 (QRICH1) as a regulator of CARD11 signaling that mediates an intracellular checkpoint for CD8+ T cell activation. QRICH1 associates with CARD11 after TCR engagement and negatively regulates CARD11 signaling to NF-κB. QRICH1 binding to CARD11 is controlled by an autoregulatory intramolecular interaction between QRICH1 domains of previously uncharacterized function. QRICH1 controls the antigen-induced activation, proliferation, and effector status of CD8+ T cells by regulating numerous genes critical for CD8+ T cell function. Our results define a component of antigen receptor signaling circuitry that fine-tunes effector output in response to antigen recognition.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins* / immunology
  • CARD Signaling Adaptor Proteins* / metabolism
  • CD8-Positive T-Lymphocytes* / immunology
  • Guanylate Cyclase* / immunology
  • Guanylate Cyclase* / metabolism
  • Humans
  • Lymphocyte Activation* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / immunology

Substances

  • CARD Signaling Adaptor Proteins
  • Guanylate Cyclase
  • Card11 protein, mouse
  • Receptors, Antigen, T-Cell
  • CARD11 protein, human