CD28 and CTLA-4 coreceptor expression and signal transduction

By C. E. Rudd, Alison Taylor, H. Schneider. Immunological Reviews, 2009

867 citations recorded by the source corpus.

Summary:  T‐cell activation is mediated by antigen‐specific signals from the TCRζ/CD3 and CD4–CD8–p56lck complexes in combination with additional co‐signals provided by coreceptors such as CD28, inducible costimulator (ICOS), cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4), programmed death (PD‐1), and others. CD28 and ICOS provide positive signals that promote and sustain T‐cell responses, while CTLA‐4 and PD‐1 limit responses. The balance between stimulatory and inhibitory co‐signals determines the ultimate nature of T‐cell responses where response to foreign pathogen is achieved without excess inflammation and autoimmunity. In this review, we outline the current knowledge of the CD28 and CTLA‐4 signaling mechanisms [involving phosphatidylinositol 3 kinase (PI3K), growth factor receptor‐bound protein 2 (Grb2), Filamin A, protein kinase C θ (PKCθ), and phosphatases] that control T‐cell immunity. We also present recent findings on T‐cell receptor‐interacting molecule (TRIM) regulation of CTLA‐4 surface expression, and a signaling pathway involving CTLA‐4 activation of PI3K and protein kinase B (PKB)/AKT by which cell survival is ensured under conditions of anergy induction.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/81f3049b56dd82ae9f9255c6d4f9750d745c8b08

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In Immunology

1. D. Pardoll
2. S. Topalian
3. Charles G. Drake
4. A. Otsuka
5. A. Korman
6. K. Kabashima
7. J. Seidel
8. J. Wolchok

Citations in the corpus

• Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, background): “Although both receptors bind CD80 and CD86, CTLA-4 does so with much higher affinity, effectively outcompeting CD28 (23).”
• Immune Checkpoint Inhibitors in Cancer Therapy (2022, background): “CTLA-4 primarily inhibits the function of CD28, a T-cell costimulatory receptor [74].”
• Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells (2013, background): “Among the earliest and best-characterized T-cell costimulatory and coinhibitory molecules are CD28 and CTLA-4 (1).”
• Neoadjuvant checkpoint blockade for cancer immunotherapy (2020, neutral): “1016/S1470-2045(19)30332-8; pmid: 31267972”
• Immunotherapy for glioma: current management and future application. (2020, neutral): “Since CTLA-4 has higher a ffi nities for both ligands than does CD28, it competitively inhibits the activation of CD28, leading to the suppression of T-cell activity [39].”
• Immune checkpoint blockade: a common denominator approach to cancer therapy (2015, background): “The specific signaling pathways by which CTLA-4 inhibits T cell activation are still under investigation, although activation of the phosphatases SHP2 and PP2A appears to be important in counteracting both tyrosine and serine/threonine kinase signals induced by TCR and CD28 (Rudd et al., 2009).”
• Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “When cells become cancerous, they will exploit this inhibitory pathway to escape the siege of the immune system [15, 16].”
• Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4 (2019, background): “CTLA-4 is not detectable in naïve T cell but is rapidly induced upon T cell activation and it primarily regulates the amplitude of T cell during the early priming phase in lymphoid organs [29, 30].”