T lymphocyte activation and apoptosis laboratory


Exosomes are small membrane vesicles (nanovesicles) formed by inward budding of the limiting membrane of late endosomes into their lumen. The exosomes accumulate as intraluminal vesicles into secretory vesicles/multivesicular bodies (MVBs). The stimulation of cells from diverse lineages induces the fusion of the limiting membrane of the MVBs with the plasma membrane and the secretion of exosomes (Fig. 1). Several evidences support the hypothesis that exosomes represent a novel modality of intercellular communication, particullarly in the immune system. In the immune system, T lymphocyte activation with antigen through the T-cell receptor (TCR) induces the acquisition of essential effector functions and controls the activation, proliferation and apoptosis of T lymphocytes. In some of these biological responses, which include the cytotoxic activity exerted by cytotoxic T lymphocytes (CTLs), T lymphocyte activation and activation-induced cell death (AICD) processes, the exosomes appear to play an important role. The MVBs from cytotoxic T lymphocytes (CTLs) are called lytic granules (Fig. 1). Upon challenge with antigen, CTLs develop different mechanisms to induce the apoptosis of target cells. Included among these strategies, the inducible expression of Fas ligand (FasL) in lytic granules and its polarized secretion at the immune synapse are thought to be important mediators of CTL-mediated killing. In addition, FasL contributes to the homeostatic control of the T lymphoid compartment that occurs through activation-induced cell death (AICD). Regarding FasL function, it has been shown that the secretion of bioactive (apoptosis-inducer) FasL into exosomes constitutes an important mechanism controlling FasL activity. Therefore, our aims are:
1) To gain insights into the mechanisms by which T lymphocytes control the polarised traffic of MVBs/lytic granules and regulate the secretion of exosomes.
2) To establish the role of pro-apoptotic exosomes in the cytotoxicity mediated by CTLs and homeostatic AICD.
With all these knowledge in hand, it will be eventually possible to modulate crucial immune functions such as CTL-mediated apoptosis and the homeostatic control of the T lymphocyte compartment.

Izquierdo Pastor, Manuel
Investigador Científico