Caracterización de una ruta fagocítica mediada por el TCR en linfocitos T

Abstract

The immunological synapse (IS) was first described as a highly specialized junction between the membranes of T cells and antigen-presenting cells. The IS was proposed to be a site for effective T cell activation, for sustained T cell receptor (TCR) engagement and signaling, and for polarized secretion into the synaptic space. However, several studies have proposed that the IS is a site for TCR endocytosis, resulting in termination of its signalling and degradation. In resting T cells, the TCR is continuously endocytosed and re-expressed at the cell surface. However, engagement with peptide-MHC (pMHC) causes increased TCR internalization, decreased recycling and increased degradation. Clathrin-dependent endocytosis is one of the mechanisms by which the TCR is internalized, both in untriggered and TCR triggered cells. However, the TCR is also internalized by clathrin-independent mechanisms that share a common cholesterol dependency but are not yet molecularly characterized. Another consequence of IS formation is the intercellular transfer of APC membrane proteins to the T cell. T cells acquire major histocompatibility complex (MHC) class I and class II from APCs, as well as co-stimulatory molecules and patches of membrane, by a mechanism most commonly referred to as trogocytosis. MHC transfer to the T cell is dependent on TCR triggering. The consequences and physiological meaning of such transfer are not completely understood. T cells that acquire pMHC from APCs can themselves become antigen-presenting cells, but it is still unclear what advantage such a T cell APC could offer in comparison with ¿professional¿ APCs. TC21 (RRas2), a small GTPase, activates phosphoinositide 3 kinase (PI3K), probably through the direct binding and recruitment of the hematopoietic specific catalytic subunit p110¿. Indeed, TC21 binds directly to the TCR and BCR (B cell antigen receptor) and it is necessary for the recruitment of p110¿ to both antigen receptors in resting cells. TC21 is constitutively associated to the TCR and BCR and it has been shown to co-translocate with the TCR to the IS. In this study, we have further investigated the role of TC21 in the formation of the IS. We found that TC21 is necessary for TCR internalization from the IS by a clathrin-independent mechanism that is nevertheless dependent on the small GTPase RhoG, previously associated with phagocytosis. Indeed, we found that T cells phagocytose 1-6 mm beads coated with anti-TCR antibodies through a TC21 and RhoG-dependent pathway, in which PI3K and actin play an important role. Since TC21-deficient and RhoG-deficient T cells are unable to trogocytose MHC class II and membrane fragments from the APC, we propose that the TCR is internalized from the IS by phagocytosis (clathrin independent process) allowing acquisition of material (eg. pMHC) from the APC. Through this process, the T cell is converted into an efficient APC