Parsing digital or analog TCR performance through piconewton forces

Aoi Akitsu; Eiji Kobayashi; Yinnian Feng; Hannah M. Stephens; Kristine N. Brazin; Daniel J. Masi; Evan H. Kirkpatrick; Robert J. Mallis; Jonathan S. Duke-Cohan; Matthew A. Booker; Vincenzo Cinella; William W. Feng; Elizabeth L. Holliday; Jonathan J. Lee; Katarzyna J. Zienkiewicz; Michael Y. Tolstorukov; Wonmuk Hwang; Matthew J. Lang; Ellis L. Reinherz

doi:10.1126/sciadv.ado4313

Parsing digital or analog TCR performance through piconewton forces

Aoi Akitsu, Eiji Kobayashi, Yinnian Feng, Hannah M. Stephens, Kristine N. Brazin, Daniel J. Masi, Evan H. Kirkpatrick, Robert J. Mallis, Jonathan S. Duke-Cohan, Matthew A. Booker, Vincenzo Cinella, William W. Feng, Elizabeth L. Holliday, Jonathan J. Lee, Katarzyna J. Zienkiewicz, Michael Y. Tolstorukov, Wonmuk Hwang, Matthew J. Lang^*, Ellis L. Reinherz^*

^*Corresponding author for this work

Immunology

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

αβ T cell receptors (TCRs) principally recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP366-374/Db and PA224-233/Db, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker up-regulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies.

Original language	English
Article number	ado4313
Journal	Science Advances
Volume	10
Issue number	33
DOIs	https://doi.org/10.1126/sciadv.ado4313
State	Published - 2024/08

ASJC Scopus subject areas

General

Access to Document

10.1126/sciadv.ado4313

Cite this

Akitsu, A., Kobayashi, E., Feng, Y., Stephens, H. M., Brazin, K. N., Masi, D. J., Kirkpatrick, E. H., Mallis, R. J., Duke-Cohan, J. S., Booker, M. A., Cinella, V., Feng, W. W., Holliday, E. L., Lee, J. J., Zienkiewicz, K. J., Tolstorukov, M. Y., Hwang, W., Lang, M. J., & Reinherz, E. L. (2024). Parsing digital or analog TCR performance through piconewton forces. Science Advances, 10(33), Article ado4313. https://doi.org/10.1126/sciadv.ado4313

@article{37fed210df7144bf9a54db8cc1f67e07,

title = "Parsing digital or analog TCR performance through piconewton forces",

abstract = "αβ T cell receptors (TCRs) principally recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP366-374/Db and PA224-233/Db, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker up-regulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies.",

author = "Aoi Akitsu and Eiji Kobayashi and Yinnian Feng and Stephens, {Hannah M.} and Brazin, {Kristine N.} and Masi, {Daniel J.} and Kirkpatrick, {Evan H.} and Mallis, {Robert J.} and Duke-Cohan, {Jonathan S.} and Booker, {Matthew A.} and Vincenzo Cinella and Feng, {William W.} and Holliday, {Elizabeth L.} and Lee, {Jonathan J.} and Zienkiewicz, {Katarzyna J.} and Tolstorukov, {Michael Y.} and Wonmuk Hwang and Lang, {Matthew J.} and Reinherz, {Ellis L.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors.",

year = "2024",

month = aug,

doi = "10.1126/sciadv.ado4313",

language = "英語",

volume = "10",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "33",

}

Akitsu, A, Kobayashi, E, Feng, Y, Stephens, HM, Brazin, KN, Masi, DJ, Kirkpatrick, EH, Mallis, RJ, Duke-Cohan, JS, Booker, MA, Cinella, V, Feng, WW, Holliday, EL, Lee, JJ, Zienkiewicz, KJ, Tolstorukov, MY, Hwang, W, Lang, MJ & Reinherz, EL 2024, 'Parsing digital or analog TCR performance through piconewton forces', Science Advances, vol. 10, no. 33, ado4313. https://doi.org/10.1126/sciadv.ado4313

TY - JOUR

T1 - Parsing digital or analog TCR performance through piconewton forces

AU - Akitsu, Aoi

AU - Kobayashi, Eiji

AU - Feng, Yinnian

AU - Stephens, Hannah M.

AU - Brazin, Kristine N.

AU - Masi, Daniel J.

AU - Kirkpatrick, Evan H.

AU - Mallis, Robert J.

AU - Duke-Cohan, Jonathan S.

AU - Booker, Matthew A.

AU - Cinella, Vincenzo

AU - Feng, William W.

AU - Holliday, Elizabeth L.

AU - Lee, Jonathan J.

AU - Zienkiewicz, Katarzyna J.

AU - Tolstorukov, Michael Y.

AU - Hwang, Wonmuk

AU - Lang, Matthew J.

AU - Reinherz, Ellis L.

PY - 2024/8

Y1 - 2024/8

N2 - αβ T cell receptors (TCRs) principally recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP366-374/Db and PA224-233/Db, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker up-regulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies.

AB - αβ T cell receptors (TCRs) principally recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP366-374/Db and PA224-233/Db, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker up-regulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies.

UR - http://www.scopus.com/inward/record.url?scp=85201336045&partnerID=8YFLogxK

U2 - 10.1126/sciadv.ado4313

DO - 10.1126/sciadv.ado4313

M3 - 学術論文

C2 - 39141734

AN - SCOPUS:85201336045

SN - 2375-2548

VL - 10

JO - Science Advances

JF - Science Advances

IS - 33

M1 - ado4313

ER -

Parsing digital or analog TCR performance through piconewton forces

Abstract

ASJC Scopus subject areas

Access to Document

Fingerprint

Cite this