The Role of the Transmembrane Alpha-Helix of Human Phospholipid Scramblase 1 in Protein Structure and Function

The Serial Engagement Model 17 Years After: From TCR Triggering to Immunotherapy

“…This analysis showed that 2-D dissociation rates are comparable to 3-D dissociation rates when measured in a cell free system such as this, supporting the idea that accelerated 2-D dissociations of TCR/pMHC bonds found in other studies (Huang et al, 2010; Huppa et al, 2010), result from active cellular dynamics. Robert et al (2012) also found that T cell activation increases with a longer binding half-life, but negatively correlates with bond mechanical strength. As discussed below, these results reconcile SPR measurements (reporting that ligand potency increases with binding half-life, Holler et al, 2001; Tian et al, 2007) with the requirement of rapid bond disruption and re-formation for serial TCR triggering (Valitutti and Lanzavecchia, 1997).…”

“…Finally, in a recent and detailed study, Robert et al used TCR coated microbeads in laminar flow chambers and measured their interaction with surface-immobilized pMHC under cell free conditions (Pierres et al, 1996; Robert et al, 2012). This analysis showed that 2-D dissociation rates are comparable to 3-D dissociation rates when measured in a cell free system such as this, supporting the idea that accelerated 2-D dissociations of TCR/pMHC bonds found in other studies (Huang et al, 2010; Huppa et al, 2010), result from active cellular dynamics.…”

“…Optimal TCR ligands would have long enough half-lives to trigger receptors but low mechanical strength. Together, these parameters would allow TCR/pMHC bonds to rapidly dissociate and reform within dynamic T cell/APC contacts thus enhancing serial TCR triggering (Ma and Finkel, 2010; Robert et al, 2012). It is interesting to note that this view goes back to initial observations showing that a functional actin cytoskeleton and T cell motility are instrumental for sustained signaling in T cells triggered by cell-bound ligands (Valitutti et al, 1995a).…”

“…Collectively, these observations cast doubts on the idea that serial TCR engagement might actually contribute to the high level of sensitivity characteristic of T lymphocyte responses. Nevertheless, recent studies in which two-dimensional (2-D) binding parameters of TCR interaction with pMHC were considered, provided data in support of the idea that TCR/pMHC binding might be sequential, thus reopening the discussion on whether serial TCR engagement might take place at the T cell/APC contact site (Huang et al, 2010; He and Bongrand, 2012; Robert et al, 2012). …”