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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen

Melissa Lever1, Hong-Sheng Lim1, Philipp Kruger1

  • 1Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|October 6, 2016
PubMed

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

Keywords:
T-cell receptorimmunologypathway architecturesignalingsystems biology

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