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 journalArticleResearchpeer-review

2 Citations (Scopus)

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 CD3 0 mice. We found that CD3 0 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
Article numbereaal2201
Number of pages15
JournalScience Immunology
Volume4
Issue number32
DOIs
Publication statusPublished - 15 Feb 2019

Cite this

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 TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network. Science Immunology, 4(32), [eaal2201]. 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, Eva M. ; Limper, Andrew H. ; 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 TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network. In: Science Immunology. 2019 ; Vol. 4, No. 32.
@article{9d230cb2c0de40d391b07fbd48c9a2c3,
title = "The early proximal TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network",
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 CD3 0 mice. We found that CD3 0 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.",
author = "Neier, {Steven C.} and Alejandro Ferrer and Wilton, {Katelynn M.} and Smith, {Stephen E.P.} and Kelcher, {April M.H.} and Pavelko, {Kevin D.} and Canfield, {Jenna M.} and Davis, {Tessa R.} and Stiles, {Robert J.} and Zhenjun Chen and James McCluskey and Burrows, {Scott R.} and Jamie Rossjohn and Hebrink, {Deanne M.} and Carmona, {Eva M.} and Limper, {Andrew H.} and Kappes, {Dietmar J.} and Wettstein, {Peter J.} and Johnson, {Aaron J.} and Pease, {Larry R.} and Daniels, {Mark A.} and Claudia Neuhauser and Diana Gil and Schrum, {Adam G.}",
year = "2019",
month = "2",
day = "15",
doi = "10.1126/sciimmunol.aal2201",
language = "English",
volume = "4",
journal = "Science Immunology",
issn = "2470-9468",
publisher = "American Association for the Advancement of Science (AAAS)",
number = "32",

}

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, EM, Limper, AH, Kappes, DJ, Wettstein, PJ, Johnson, AJ, Pease, LR, Daniels, MA, Neuhauser, C, Gil, D & Schrum, AG 2019, 'The early proximal TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network', Science Immunology, vol. 4, no. 32, eaal2201. https://doi.org/10.1126/sciimmunol.aal2201

The early proximal 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, Eva M.; Limper, Andrew H.; 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, eaal2201, 15.02.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The early proximal TCR signalosome specifies thymic selection outcome through a quantitative protein interaction network

AU - Neier, Steven C.

AU - Ferrer, Alejandro

AU - Wilton, Katelynn M.

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, Eva M.

AU - Limper, Andrew H.

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.

PY - 2019/2/15

Y1 - 2019/2/15

N2 - 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 CD3 0 mice. We found that CD3 0 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.

AB - 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 CD3 0 mice. We found that CD3 0 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.

UR - http://www.scopus.com/inward/record.url?scp=85061575011&partnerID=8YFLogxK

U2 - 10.1126/sciimmunol.aal2201

DO - 10.1126/sciimmunol.aal2201

M3 - Article

C2 - 30770409

AN - SCOPUS:85061575011

VL - 4

JO - Science Immunology

JF - Science Immunology

SN - 2470-9468

IS - 32

M1 - eaal2201

ER -