LAUSR

HighlightsThe Notch activation may be cis or trans ligand‐dependent which are regulated by TCR signalling on human &agr;&bgr; T cells.Notch signalling has the ability to affect both the proximal and distal TCR signalling events.Inhibition of Notch signalling induces GRAIL which might be an essential regulator of CD3‐&zgr; chain expression in T cells. ABSTRACT The Notch signalling pathway is an important regulator of T cell function and is known to regulate the effector functions of T cells driven by T cell receptor (TCR). However, the mechanism integrating these pathways in human CD3+ &agr;&bgr; T cells is not well understood. The present study was carried out to investigate how Notch and TCR driven signalling are synchronized in human &agr;&bgr; T cells. Differential expression of Notch receptors, ligands, and target genes is observed on human &agr;&bgr; T cells which are upregulated on stimulation with &agr;‐CD3/CD28 mAb. Inhibition of Notch signalling by GSI‐X inhibited the activation of T cells and affected proximal T cell signalling by regulating CD3‐&zgr; chain expression. Inhibition of Notch signalling decreased the protein expression of CD3‐&zgr; chain and induced expression of E3 ubiquitin ligase (GRAIL) in human &agr;&bgr; T cells. Apart from affecting proximal TCR signalling, Notch signalling also regulated the distal TCR signalling events. In the absence of Notch signalling, &agr;‐CD3/CD28 mAb induced activation and IFN‐&ggr; production by &agr;&bgr; T cells was down‐modulated. The absence of Notch signalling in human &agr;&bgr; T cells inhibited proliferative responses despite strong signalling through TCR and IL‐2 receptor. This study shows how Notch signalling cooperates with TCR signalling by regulating CD3‐&zgr; chain expression to support proliferation and activation of human &agr;&bgr; T cells.