The early proximal αβ 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 Porquera, Andrew Harold 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

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Abstract

During αβ 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 αβ 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 CD3δ, we reexamined the block in positive selection observed in CD3δ0 mice. We found that CD3δ0 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent αβ T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3δ in positive selection is to quantitatively boost the signal for maximal generation of αβ 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)
JournalScience immunology
Volume4
Issue number32
DOIs
StatePublished - Feb 15 2019

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Protein Interaction Maps
T-Cell Antigen Receptor
Proteins
T-Lymphocytes
Thymocytes
Cell Differentiation
Cell Death

ASJC Scopus subject areas

  • Medicine(all)

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Neier, S. C., Ferrer, A., Wilton, K. M., Smith, S. E. P., Kelcher, A. M. H., Pavelko, K. D., ... Schrum, A. G. (2019). The early proximal αβ TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network. Science immunology, 4(32). https://doi.org/10.1126/sciimmunol.aal2201

The early proximal αβ TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network. / Neier, Steven C.; Ferrer, Alejandro; Wilton, Katelynn M.; Smith, Stephen E.P.; Kelcher, April M.H.; Pavelko, Kevin D.; Canfield, Jenna M.; Davis, Tessa R.; Stiles, Robert J.; Chen, Zhenjun; McCluskey, James; Burrows, Scott R.; Rossjohn, Jamie; Hebrink, Deanne M.; Carmona Porquera, Eva M; Limper, Andrew Harold; Kappes, Dietmar J.; Wettstein, Peter J.; Johnson, Aaron J.; Pease, Larry R; Daniels, Mark A.; Neuhauser, Claudia; Gil, Diana; Schrum, Adam G.

In: Science immunology, Vol. 4, No. 32, 15.02.2019.

Research output: Contribution to journalArticle

Neier, SC, Ferrer, A, Wilton, KM, Smith, SEP, Kelcher, AMH, Pavelko, KD, Canfield, JM, Davis, TR, Stiles, RJ, Chen, Z, McCluskey, J, Burrows, SR, Rossjohn, J, Hebrink, DM, Carmona Porquera, EM, Limper, AH, Kappes, DJ, Wettstein, PJ, Johnson, AJ, Pease, LR, Daniels, MA, Neuhauser, C, Gil, D & Schrum, AG 2019, 'The early proximal αβ TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network', Science immunology, vol. 4, no. 32. https://doi.org/10.1126/sciimmunol.aal2201
Neier, Steven C. ; Ferrer, Alejandro ; Wilton, Katelynn M. ; Smith, Stephen E.P. ; Kelcher, April M.H. ; Pavelko, Kevin D. ; Canfield, Jenna M. ; Davis, Tessa R. ; Stiles, Robert J. ; Chen, Zhenjun ; McCluskey, James ; Burrows, Scott R. ; Rossjohn, Jamie ; Hebrink, Deanne M. ; Carmona Porquera, Eva M ; Limper, Andrew Harold ; Kappes, Dietmar J. ; Wettstein, Peter J. ; Johnson, Aaron J. ; Pease, Larry R ; Daniels, Mark A. ; Neuhauser, Claudia ; Gil, Diana ; Schrum, Adam G. / The early proximal αβ TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network. In: Science immunology. 2019 ; Vol. 4, No. 32.
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AU - Neier, Steven C.

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AU - Smith, Stephen E.P.

AU - Kelcher, April M.H.

AU - Pavelko, Kevin D.

AU - Canfield, Jenna M.

AU - Davis, Tessa R.

AU - Stiles, Robert J.

AU - Chen, Zhenjun

AU - McCluskey, James

AU - Burrows, Scott R.

AU - Rossjohn, Jamie

AU - Hebrink, Deanne M.

AU - Carmona Porquera, Eva M

AU - Limper, Andrew Harold

AU - Kappes, Dietmar J.

AU - Wettstein, Peter J.

AU - Johnson, Aaron J.

AU - Pease, Larry R

AU - Daniels, Mark A.

AU - Neuhauser, Claudia

AU - Gil, Diana

AU - Schrum, Adam G.

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N2 - During αβ 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 αβ 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 CD3δ, we reexamined the block in positive selection observed in CD3δ0 mice. We found that CD3δ0 thymocytes were inhibited but capable of signaling positive selection, generating low numbers of MHC-dependent αβ T cells that expressed diverse TCR repertoires and participated in immune responses against infection. We conclude that the major role for CD3δ in positive selection is to quantitatively boost the signal for maximal generation of αβ T cells. Together, these data indicate that a quantitative network signaling mechanism through the early proximal TCR signalosome determines thymic selection outcome.

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