Existencia de oligómeros preformados de MHC y TCR y su implicación en la sensibilidad de la respuesta de los linfocitos T

Resumen

T cell activation requires the interaction of the TCR with its ligand, a peptide bound to a MHC molecule. This interaction is characterized by paradoxical properties: exquisite specificity by a receptor of low affinity that must detect and respond to a small proportion of MHC molecules loaded with antigenic peptides within a much larger pool of MHC molecules presenting self-peptides. This leads to the consideration how T cells find antigenic peptides with sufficient density to cause its activation. In this study we have shown the existence of preformed oligomeric TCR and MHC complexes on the cell surface, and the involvement of such complexes in the sensitivity of the T cell response. First, we have shown that pre-activated T cells have a more and bigger preformed oligomeric TCR complexes than naïve T cells. Also we have found a correlation between the TCR oligomeric enrichment and an increased T cell sensitivity. Secondly, we have shown the existence of MHC clusters loaded with the antigen peptide in antigen presenting cells loaded with soluble peptide, but more importantly, we found that MHCp concentrates in few discrete areas of the plasma membrane in cells infected with an antigen-encoding virus. The existence of these clusters could explain how T cells are able to find a specific antigenic peptide with sufficient density as to promote TCR crosslinking. Since, as we previously described, pre-activated and memory T cells have bigger TCR nanoclusters than naïve T cells, the question emerges how the size of TCR oligomers is regulated in the transition from naïve to memory T cells. In this thesis we show that the relative amount of the TCR-associated CD3¿ chain in pre-activated T cells is lower than in naïve T cells, suggesting that the amount of CD3¿ could regulate the extent of TCR oligomerization. In support of this notion we show that over-expression of the CD3¿ chain reduces the size of TCR oligomers coincident with increased total TCR expression at the cell surface. Together, these results support a model in which during naïve-memory differentiation T cells undergo a CD3¿-regulated change of TCR stoichiometry that results in a process of ¿avidity maturation¿.