αβ T Cell Receptor Mechanosensing Forces out Serial Engagement

Yinnian Feng, Ellis L. Reinherz, Matthew J. Lang
2018 Trends in immunology  
T lymphocytes use αb T cell receptors (TCRs) to recognize sparse antigenic peptides bound to MHC molecules (pMHCs) arrayed on antigen-presenting cells (APCs). Contrary to conventional receptor-ligand associations exemplified by antigen-antibody interactions, forces play a crucial role in nonequilibrium mechanosensor-based T cell activation. Both T cell motility and local cytoskeleton machinery exert forces (i.e., generate loads) on TCR-pMHC bonds. We review biological features of the
more » ... ent activation process as revealed by optical tweezers single molecule/single cell and other biophysical measurements. The findings link pMHC-triggered TCRs to single cytoskeletal motors; define the importance of energized anisotropic (i.e., force direction dependent) activation; and characterize immunological synapse formation as digital, revealing no serial requirement. The emerging picture suggests new approaches for the monitoring and design of cytotoxic T lymphocyte (CTL)based immunotherapy. Biophysical Mechanism of αb TCR Triggering via an Energized Process αb T cells specifically recognize foreign peptides displayed on infected or otherwise perturbed cells through a process that discriminates with exquisite specificity. In so doing, T cells can discern a single amino acid difference between two antigens. At the heart of this process is a receptor-ligand interaction between variable domains on the αb TCR and a peptide cradled in the groove of a major histocompatibility molecule, pMHC ([1,2] and references therein). APCs displaying peptides at single-molecule (SM) levels can be recognized by T cells [3, 4] . Equilibrium between a bound and unbound receptor satisfies the law of mass action and mathematically relates the relative population of species found in the bound and unbound states; the ratio of the forward and reverse state transitions; or similarly the ratio of the state lifetimes. From an equilibrium perspective and our basic understanding of receptor-ligand associations, one expects high affinity. Paradoxically, however, TCR-pMHC affinities as conventionally measured by free-solution methods such as surface plasmon resonance reveal low affinity receptorligand interactions; typically in the low to high micromolar 3D affinity range. Notwithstanding, the paradox that a mere handful of foreign peptides is sufficient for CTLs to mount a deadly response or helper T cells to activate despite apparent weak affinity was thought to be explained through a concept known as serial engagement [5] . Conceptualized 25 years ago, serial engagement (or serial triggering) recycles a single pMHC through multiple sequential TCR binding events to collectively stimulate a T cell over a time period (from seconds to hours) [6] . One ligand on an APC with intermediate affinity (K D = $1-5 mM) can thus activate in series a multiplicity of TCRs on a given T cell where the sum of integrated receptor activation collectively suffices to turn the T cell 'on ' [7]. A fundamental limitation of this model is that it is not based on direct visualization and continuous measurement of the in situ dynamic interactions between TCRs and pMHCs at the live cell membrane. Instead it utilizes downregulation of TCR Highlights
doi:10.1016/j.it.2018.05.005 pmid:30060805 pmcid:PMC6154790 fatcat:dbznwlegjjhaxkjbvgsyethsfe