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

T cell activation, initiated by T cell receptor (TCR) mediated recognition of pathogen-derived peptides presented by major histocompatibility complex class I or II molecules (pMHC), shows exquisite specificity and sensitivity, even though the TCR–pMHC binding interaction is of low affinity. Recent experimental work suggests that TCR pre-clustering may be a mechanism via which T cells can achieve such high sensitivity. The unresolved stoichiometry of the TCR makes TCR–pMHC binding and TCR triggering, an open question. We formulate a mathematical model to characterize the pre-clustering of T cell receptors (TCRs) on the surface of T cells, motivated by the experimentally observed distribution of TCR clusters on the surface of naive and memory T cells. We extend a recently introduced stochastic criterion to compute the timescales of T cell responses, assuming that ligand-induced cross-linked TCR is the minimum signaling unit. We derive an approximate formula for the mean time to signal initiation. Our results show that pre-clustering reduces the mean activation time. However, additional mechanisms favoring the existence of clusters are required to explain the difference between naive and memory T cell responses. We discuss the biological implications of our results, and both the compatibility and complementarity of our approach with other existing mathematical models.This work has been partially supported through Grants No. FIS2009-12964-C05-03 (Mario Castro, Grant Lythe, Carmen Molina-París), BFU2009-08009 from the Ministerio de Ciencia e Innovación (Hisse M. van Santen), FP7 PIRSES-GA-2008-230665 and PIRSES-GA-2012-317893 (Mario Castro, Grant Lythe, and Carmen Molina-París), BBSRC BB/F003811/1 (Grant Lythe and Carmen Molina-París), and BBSRC BB/G023395/1 (Carmen Molina-París).Peer reviewedPeer Reviewe