L-type voltage-gated Ca2+ channels control T cell killing via non-canonical Hedgehog signaling

Hedgehog signaling is critical for CTL-mediated killing. Remarkably the pathway cannot be induced canonically by extracellular Hedgehog ligands but instead is activated by the T cell receptor (TCR).

How the Hedgehog pathway is mechanistically activated downstream of the TCR is unknown. Here we show that L-type voltage gated Ca2+ (Cav1) channels at the plasma membrane downstream of the TCR control an extracellular Ca2+ influx leading to induction of the Hedgehog transcription factor Gli1 which is essential for efficient CTL killing in vitro and in vivo. This novel non-canonical Hedgehog pathway is independent of canonical signaling and represents a primary mechanism of Gli1 induction in naive CD8+ T cells, while CTLs can also activate Gli1 via MAPK.