2009 | Jennifer E. Smith-Garvin, Gary A. Koretzky, Martha S. Jordan
This article commemorates the 25th anniversary of the first *Annual Review in Immunology* publication on T cell antigen receptor (TCR) signaling. It begins with a historical overview of early studies that established the basic paradigm for TCR engagement and signal transduction. The review then delves into the current understanding of TCR signaling, including recent findings on crosstalk between the TCR and integrins, the role of costimulatory molecules, and negative regulation of T cell function.
The TCR complex, consisting of variable αβ chains and non-polymorphic CD3 proteins, was initially characterized through molecular techniques and immunization experiments. The CD3 proteins, particularly the ITAM-containing regions, play a crucial role in signal transduction. Early studies identified the importance of src family kinases (lck and fyn) and ZAP-70 in TCR signaling. The formation of a multi-molecular signaling complex involving LAT, SLP-76, and PLCγ1 is essential for downstream signaling pathways.
The review also discusses the proximal signaling complex, which includes the activation of PLCγ1, DAG-mediated signaling pathways involving Ras and PKC, Ca2+-mediated signaling, and actin cytoskeletal responses. These pathways are interconnected and contribute to T cell activation and polarization.
Additionally, the article explores the "inside-out" signaling pathway to integrins, where TCR signals enhance integrin activation and adhesion. Costimulation through CD28 and other receptors is crucial for avoiding anergy and promoting productive T cell activation. CD28 signaling involves PI3K-Akt pathways, which regulate cell survival, proliferation, and metabolic processes.
Overall, the review provides a comprehensive overview of the molecular and biochemical events that underlie T cell activation, highlighting the complex interplay between various signaling molecules and pathways.This article commemorates the 25th anniversary of the first *Annual Review in Immunology* publication on T cell antigen receptor (TCR) signaling. It begins with a historical overview of early studies that established the basic paradigm for TCR engagement and signal transduction. The review then delves into the current understanding of TCR signaling, including recent findings on crosstalk between the TCR and integrins, the role of costimulatory molecules, and negative regulation of T cell function.
The TCR complex, consisting of variable αβ chains and non-polymorphic CD3 proteins, was initially characterized through molecular techniques and immunization experiments. The CD3 proteins, particularly the ITAM-containing regions, play a crucial role in signal transduction. Early studies identified the importance of src family kinases (lck and fyn) and ZAP-70 in TCR signaling. The formation of a multi-molecular signaling complex involving LAT, SLP-76, and PLCγ1 is essential for downstream signaling pathways.
The review also discusses the proximal signaling complex, which includes the activation of PLCγ1, DAG-mediated signaling pathways involving Ras and PKC, Ca2+-mediated signaling, and actin cytoskeletal responses. These pathways are interconnected and contribute to T cell activation and polarization.
Additionally, the article explores the "inside-out" signaling pathway to integrins, where TCR signals enhance integrin activation and adhesion. Costimulation through CD28 and other receptors is crucial for avoiding anergy and promoting productive T cell activation. CD28 signaling involves PI3K-Akt pathways, which regulate cell survival, proliferation, and metabolic processes.
Overall, the review provides a comprehensive overview of the molecular and biochemical events that underlie T cell activation, highlighting the complex interplay between various signaling molecules and pathways.