Quantitative network signal combinations downstream of TCR activation can predict IL-2 production response

ML Kemp, L Wille, CL Lewis, LB Nicholson, DA Lauffenburger

Research output: Contribution to journalArticle (Academic Journal)peer-review

46 Citations (Scopus)

Abstract

Proximal signaling events activated by TCR-peptide/MHC (TCR-pMHC) binding have been the focus of intense ongoing study, but understanding how the consequent downstream signaling networks integrate to govern ultimate avidity-appropriate TCR-pMHC T cell responses remains a crucial next challenge. We hypothesized that a quantitative combination of key downstream network signals across multiple pathways must encode the information generated by TCR activation, providing the basis for a quantitative model capable of interpreting and predicting T cell functional responses. To this end, we measured 11 protein nodes across six downstream pathways, along five time points from 10 min to 4 h, in a 1B6 T cell hybridoma stimulated by a set of three myelin proteolipid protein 139-151 altered peptide ligands. A multivariate regression model generated from this data compendium successfully comprehends the various IL-2 production responses and moreover successfully predicts a priori the response to an additional peptide treatment, demonstrating that TCR binding information is quantitatively encoded in the downstream network. Individual node and/or time point measurements less effectively accounted for the IL-2 responses, indicating that signals must be integrated dynamically across multiple pathways to adequately represent the encoded TCR signaling information. Of further importance, the model also successfully predicted a priori direct experimental tests of the effects of individual and combined inhibitors of the MEK/ERK and PI3K/Akt pathways on this T cell response. Together, our findings show how multipathway network signals downstream of TCR activation quantitatively integrate to translate pMHC stimuli into functional cell responses.
Translated title of the contributionQuantitative network signal combinations downstream of TCR activation can predict IL-2 production response
Original languageEnglish
Pages (from-to)4984 - 4992
Number of pages9
JournalJournal of Immunology
Volume178 (8)
Publication statusPublished - Apr 2007

Bibliographical note

Publisher: American Association of Immunologists

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