AUTHOR=Castro Mario , van Santen Hisse M. , Férez María , Alarcón Balbino , Lythe Grant , Molina-París Carmen 

TITLE=Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms

JOURNAL=Frontiers in Immunology

VOLUME=Volume 5 - 2014

YEAR=2014

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2014.00132

DOI=10.3389/fimmu.2014.00132

ISSN=1664-3224

ABSTRACT=T~cell activation, initiated by T~cell receptor (TCR) mediated<br/>  recognition of pathogen derived peptides presented by major<br/>  histocompatibility complex class I or II molecules (pMHC), shows<br/>  exquisite specificity and sensitivity, even though the TCR-pMHC<br/>  binding interaction is of low affinity.  Recent experimental work<br/>  suggests that TCR pre-clustering may be a mechanism via which<br/>  T~cells can achieve such high sensitivity.  The unresolved<br/>  stoichiometry of the TCR makes TCR-pMHC binding and TCR triggering<br/>  an open question. We formulate a mathematical model to characterise<br/>  the pre-clustering of T~cell receptors (TCRs) on the surface of<br/>  T~cells, motivated by the experimentally-observed distribution of<br/>  TCR clusters on the surface of naive and memory T~cells.  We extend<br/>  a recently-introduced stochastic criterion to compute the timescales<br/>  of T~cell responses, assuming that ligand-induced cross-linked TCR<br/>  is the minimum signalling unit.  We derive an approximate formula<br/>  for the mean time to signal initiation.  Our results show that<br/>  pre-clustering reduces the mean activation time. However, additional<br/>  mechanisms favouring the existence of clusters are required to<br/>  explain the difference between naive and memory T~cell responses.<br/>  We discuss the biological implications of our results, and both the<br/>  compatibility and complementarity of our approach with other<br/>  existing mathematical models.