Src family kinases Fyn and Lyn are constitutively activated and mediate plasmacytoid dendritic cell responses

DALLARI S; JO Y; GHOSH P; MACAL M; SWANSON L; ZUNIGA EI; LOUREIRO ME; HESSER C

NATURE COMMUNICATIONS

Macmillan Publishers Limited

Año: 2017 vol. 1483

2041-1723

Plasmacytoid dendritic cells (pDCs) are type I interferon producing cells and have critical roles in a number of human illnesses; however, their molecular regulation is incompletely understood. Here we show the role of Src family kinases (SFKs) in mouse and human pDCs. pDCs express Fyn and Lyn and their activating residues are phosphorylated both before and after Toll-like-receptor (TLR) stimulation. Fyn or Lyn genetic ablation as well as treatment with a pan-SFK inhibitor or a small molecule blocking members of the SFKs ablate pDC (but not conventional DC) responses both in vitro and in vivo. Inhibition of SFK activity not only alters TLR-ligand localization and inhibits important signalling events after TLR stimulation, but, independent of TLR signalling, also affects constitutive phosphorylation of BCAP, an adaptor protein bridging PI3K and TLR pathways. Our data identify SFK Fyn and Lyn as important factors that promote pDC responses, describe the mechanisms involved and highlight a tonic SFK-mediated signalling that precedes pathogen encounter, raising the possibility that small molecules targeting SFKs could modulate pDC responses in human diseases.