The early proximal TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network

Steven C. Neier, Alejandro Ferrer, Katelynn M. Wilton, Stephen E.P. Smith, April M.H. Kelcher, Kevin D. Pavelko, Jenna M. Canfield, Tessa R. Davis, Robert J. Stiles, Zhenjun Chen, James McCluskey, Scott R. Burrows, Jamie Rossjohn, Deanne M. Hebrink, Eva M. Carmona, Andrew H. Limper, Dietmar J. Kappes, Peter J. Wettstein, Aaron J. Johnson, Larry R. PeaseMark A. Daniels, Claudia Neuhauser, Diana Gil, Adam G. Schrum

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

During T cell development, T cell antigen receptor (TCR) engagement transduces biochemical signals through a protein-protein interaction (PPI) network that dictates dichotomous cell fate decisions. It remains unclear how signal specificity is communicated, instructing either positive selection to advance cell differentiation or death by negative selection. Early signal discrimination might occur by PPI signatures differing qualitatively (customized, unique PPI combinations for each signal), quantitatively (graded amounts of a single PPI series), or kinetically (speed of PPI pathway progression). Using a novel PPI network analysis, we found that early TCR-proximal signals distinguishing positive from negative selection appeared to be primarily quantitative in nature. Furthermore, the signal intensity of this PPI network was used to find an antigen dose that caused a classic negative selection ligand to induce positive selection of conventional T cells, suggesting that the quantity of TCR triggering was sufficient to program selection outcome. Because previous work had suggested that positive selection might involve a qualitatively unique signal through CD3, we reexamined the block in positive selection observed in CD30 mice. We found that CD30 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3 in positive selection is to quantitatively boost the signal for maximal generation of T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.

Original languageEnglish (US)
Article numbereaal2201
JournalScience Immunology
Volume4
Issue number32
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Neier, S. C., Ferrer, A., Wilton, K. M., Smith, S. E. P., Kelcher, A. M. H., Pavelko, K. D., Canfield, J. M., Davis, T. R., Stiles, R. J., Chen, Z., McCluskey, J., Burrows, S. R., Rossjohn, J., Hebrink, D. M., Carmona, E. M., Limper, A. H., Kappes, D. J., Wettstein, P. J., Johnson, A. J., ... Schrum, A. G. (2019). The early proximal TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network. Science Immunology, 4(32), [eaal2201]. https://doi.org/10.1126/sciimmunol.aal2201