title: Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms.
abstract: 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.
authors.affiliation: Grupo de Dinámica No-Lineal and Grupo Interdisciplinar de Sistemas Complejos (GISC), Escuela Técnica Superior de Ingeniería (ICAI), Universidad Pontificia Comillas , Madrid , Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.affiliation: Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid , Madrid , Spain.
authors.forename: Hisse M
authors.initials: HM
authors.lastname: van Santen
authors.affiliation: Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid , Madrid , Spain.
authors.forename: María
authors.initials: M
authors.lastname: Férez
authors.affiliation: Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid , Madrid , Spain.
authors.forename: Balbino
authors.initials: B
authors.lastname: Alarcón
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds , Leeds , UK.
authors.forename: Grant
authors.initials: G
authors.lastname: Lythe
authors.affiliation: Department of Applied Mathematics, School of Mathematics, University of Leeds , Leeds , UK.
authors.forename: Carmen
authors.initials: C
authors.lastname: Molina-París
keywords: T cell receptor; clustering; memory T cells; naive T cells; signaling; stochastic dynamics