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

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.
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Submitted on : Tuesday, May 9, 2017 - 12:30:10 PM
Last modification on : Thursday, October 22, 2020 - 3:12:05 PM
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Jérôme Bouchet, Iratxe del Río-Iñiguez, Elena Vázquez-Chávez, Rémi Lasserre, Sonia Agüera-González, et al.. Rab11-FIP3 Regulation of Lck Endosomal Traffic Controls TCR Signal Transduction.. Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2017, pp.2967-2978. ⟨10.4049/jimmunol.1600671⟩. ⟨pasteur-01519813⟩

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