Abstract EN:

The immunological synapse is the result of a T cell polarization process that depends on the orchestrated action of the actin and microtubule cytoskeleton and of intracellular vesicle traffic. The T cell antigen receptor (TCR) and various components of its proximal signaling machinery are associated with the plasma membrane and vesicular endosomal compartments, continuously trafficking between the two locations. I show in this thesis that the subcellular localization and function of the tyrosine kinase Lck and the actin cytoskeleton regulator Rac1, depend on the Rab11 recycling endosomal compartment, and more in particular, on the Rab11 effector FIP3. Importantly, FIP3-dependent Lck and Rac1 localization controls early TCR signaling, intracellular calcium concentration, IL-2 gene expression and morphological events, like T cell spreading and synapse symmetry. Moreover, I investigated how the HIV-1 accessory protein Nef, which is crucial for virus replication in vivo and AIDS pathogenesis, specifically hijacks several active signaling molecules, concentrating them in the Rab11 endosomal compartment, and concomitantly inducing the upregulation of some early and late T cell activation genes. Interestingly, dispersion of this concentration by depleting Rab11-FIP3, counteracted Nef-induced gene expression upregulation. Therefore, by modifying their endosomal traffic, Nef hijacks signaling and actin cytoskeleton regulators to dually modulate their functional outputs. In conclusion, our data shed new light into the molecular mechanisms orchestrating endosomal traffic with T cell activation and cytoskeletal rearrangements, and their subversion during HIV-1 infection.