Parsing digital or analog TCR performance through piconewton forces

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, TC...

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Bibliographic Details
Published in:Science advances 2024-08, Vol.10 (33), p.eado4313
Main Authors: Akitsu, Aoi, Kobayashi, Eiji, Feng, Yinnian, Stephens, Hannah M, Brazin, Kristine N, Masi, Daniel J, Kirkpatrick, Evan H, Mallis, Robert J, Duke-Cohan, Jonathan S, Booker, Matthew A, Cinella, Vincenzo, Feng, William W, Holliday, Elizabeth L, Lee, Jonathan J, Zienkiewicz, Katarzyna J, Tolstorukov, Michael Y, Hwang, Wonmuk, Lang, Matthew J, Reinherz, Ellis L
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Humans
Immunology
Influenza A virus - immunology
Lymphocyte Activation - immunology
Mice
Optical Tweezers
Orthomyxoviridae Infections - immunology
Orthomyxoviridae Infections - virology
Receptors, Antigen, T-Cell - immunology
Receptors, Antigen, T-Cell - metabolism
Receptors, Antigen, T-Cell, alpha-beta - chemistry
Receptors, Antigen, T-Cell, alpha-beta - metabolism
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Summary: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 (NP /D and PA /D , 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.ado4313