Send to

Choose Destination
J Immunol. 2017 Apr 1;198(7):2967-2978. doi: 10.4049/jimmunol.1600671. Epub 2017 Feb 24.

Rab11-FIP3 Regulation of Lck Endosomal Traffic Controls TCR Signal Transduction.

Author information

Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France;
CNRS URA1961, 75724 Paris Cedex 15, France.
INSERM U1221, 75724 Paris Cedex 15, France; and.
Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.
Molecular Cell Biology Laboratory, School of Biochemistry and Cell Biology, Biosciences Institute, University College Cork, Cork, Ireland.


The role of endosomes in receptor signal transduction is a long-standing question, which remains largely unanswered. The T cell Ag receptor and various components of its proximal signaling machinery are associated with distinct endosomal compartments, but how endosomal traffic affects T cell signaling remains ill-defined. In this article, we demonstrate in human T cells that the subcellular localization and function of the protein tyrosine kinase Lck depends on the Rab11 effector FIP3 (Rab11 family interacting protein-3). FIP3 overexpression or silencing and its ability to interact with Rab11 modify Lck subcellular localization and its delivery to the immunological synapse. Importantly, FIP3-dependent Lck localization controls early TCR signaling events, such as tyrosine phosphorylation of TCRζ, ZAP70, and LAT and intracellular calcium concentration, as well as IL-2 gene expression. Interestingly, FIP3 controls both steady-state and poststimulation phosphotyrosine and calcium levels. Finally, our findings indicate that FIP3 modulates TCR-CD3 cell surface expression via the regulation of steady-state Lck-mediated TCRζ phosphorylation, which in turn controls TCRζ protein levels. This may influence long-term T cell activation in response to TCR-CD3 stimulation. Therefore, our data underscore the importance of finely regulated endosomal traffic in TCR signal transduction and T cell activation leading to IL-2 production.

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center