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.
Keywords: T cell receptor, clustering, stochastic dynamics, signaling, naive T cells, memory T cells
JCR Impact Factor and WoS quartile: Q2 (2014); 5.085 - Q1 (2019)
DOI reference: 10.3389/fimmu.2014.00132
Published on-line: .
M. Castro, H.M. Van Santen, M. Férez, B. Alarcón, G. Lythe, C. Molina-Paris. Receptor pre-clustering and T cell responses: insights into molecular mechanisms. Frontiers in Immunology. April 2014 [Online]