Functional exhaustion of human follicular cytotoxic T cells is associated with CEACAM1 expression and dysregulation of the SHP1–LCK–ZAP70 signaling axis
In vitro study reveals CEACAM1-driven SHP1 signaling mediates follicular cytotoxic T cell exhaustion, highlighting a therapeutic target to restore antitumor immunity.
Key Points
To investigate the molecular mechanisms governing the functional exhaustion of human follicular cytotoxic T cells and evaluate the role of CEACAM1 and downstream signaling intermediates.
Generated in vitro-differentiated human follicular cytotoxic T (Tfc) cells using cell culture models to examine phenotype and effector functions.
Performed genetic and pharmacological modulation of the SHP-1/LCK/ZAP70 signaling cascade in CEACAM1-positive Tfc cells to assess signal restoration.
CEACAM1 expression was enriched on dysfunctional Tfc cells and strongly associated with impaired cytotoxicity and defective B cell helper functions.
CEACAM1 expression correlated with heightened SHP-1 activation and depleted total LCK and ZAP70 protein abundance, disrupting proximal TCR signal transduction.
Targeting the SHP-1/LCK/ZAP70 signaling pathway partially restored proximal TCR signaling alongside cytotoxic and helper capabilities in CEACAM1-positive Tfc cells.