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Spatiotemporal receptor dynamics during early T cell signaling

  • Author(s): Fay, Nicole Cheung
  • Advisor(s): Groves, Jay T
  • Kuriyan, John
  • et al.
Abstract

A given T cell receptor (TCR) can robustly discern a pathogen-derived agonist peptide amidst a myriad of background peptides, all bound to major histocompatibility complexes (MHC). This remarkable degree of discrimination is the culmination of physical operations happening at the membrane-membrane junction between a T cell and an antigen-presenting cell. In the research described in this dissertation, I applied optical methods to hybrid interfaces between a live primary T cell and a supported lipid bilayer mimicking an antigen-presenting cell (APC) surface. In this manner, I revealed a number of novel mechanisms by which ligand-receptor dynamics dictate T cell signaling output. First, a two-parameter titration of two ligands - agonist peptide-MHC and the costimulatory surface molecule CD80/B7-1 - revealed that the density of CD80 influences the TCR activation threshold. Additionally, co-presentation led to an interdependent trafficking scheme of these surface molecules that may serve to boost the effectiveness of CD80 costimulation at low agonist peptide-MHC densities and reduce spurious activation under other conditions. Second, it was possible to resolve TCR microclusters by size using a nanoparticle array embedded in the ligand-presenting bilayer. This innovative form of size-based membrane-receptor chromatography in live cells revealed that the maximal size of the TCR microclusters was regulated by engagement with MHC molecules occupied by our model agonist peptide (moth cytochrome c). T cell antigen recognition and subsequent activation was found to be unaffected by the percolation of actively signaling TCR microclusters through this nanoparticle array. Third, myosin activity was responsible for the rapid centripetal burst of TCR microclusters in the initial 60 seconds after antigen exposure. Importantly, inhibition of myosin-induced forces abolished T cell activation, a process potentially mediated by the force-tension sensor CasL. In summary, T cell response potency results from spatiotemporal coordination of a massive interconnected signaling network undergoing continuous feedback with ligand-receptor binding events.

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