Mapping the stochastic sequence of individual ligand-receptor binding events to cellular activation: T cells act on the rare events.

Autor:	Lin JJY; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA., Low-Nam ST; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA., Alfieri KN; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA., McAffee DB; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA., Fay NC; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA., Groves JT; Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA. jtgroves@lbl.gov.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2019 Jan 15; Vol. 12 (564). Date of Electronic Publication: 2019 Jan 15.
DOI:	10.1126/scisignal.aat8715
Abstrakt:	T cell receptor (TCR) binding to agonist peptide major histocompatibility complex (pMHC) triggers signaling events that initiate T cell responses. This system is remarkably sensitive, requiring only a few binding events to successfully activate a cellular response. On average, activating pMHC ligands exhibit mean dwell times of at least a few seconds when bound to the TCR. However, a T cell accumulates pMHC-TCR interactions as a stochastic series of discrete, single-molecule binding events whose individual dwell times are broadly distributed. With activation occurring in response to only a handful of such binding events, individual cells are unlikely to experience the average binding time. Here, we mapped the ensemble of pMHC-TCR binding events in space and time while simultaneously monitoring cellular activation. Our findings revealed that T cell activation hinges on rare, long-dwell time binding events that are an order of magnitude longer than the average agonist pMHC-TCR dwell time. Furthermore, we observed that short pMHC-TCR binding events that were spatially correlated and temporally sequential led to cellular activation. These observations indicate that T cell antigen discrimination likely occurs by sensing the tail end of the pMHC-TCR binding dwell time distribution rather than its average properties. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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