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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

1
Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France; andres.alcover@pasteur.fr jerome.bouchet@inserm.fr.
2
CNRS URA1961, 75724 Paris Cedex 15, France.
3
INSERM U1221, 75724 Paris Cedex 15, France; and.
4
Department of Immunology, Lymphocyte Cell Biology Unit, Institut Pasteur, 75724 Paris, France.
5
Molecular Cell Biology Laboratory, School of Biochemistry and Cell Biology, Biosciences Institute, University College Cork, Cork, Ireland.

Abstract

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.

PMID:
28235866
DOI:
10.4049/jimmunol.1600671
[Indexed for MEDLINE]
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