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Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density
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James, John R. (2018) Tuning ITAM multiplicity on T cell receptors can control potency and selectivity to ligand density. Science Signaling, 11 (531). eaan1088. doi:10.1126/scisignal.aan1088
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Official URL: http://dx.doi.org/10.1126/scisignal.aan1088
Abstract
The T cell antigen receptor (TCR) recognizes peptides from pathogenic proteins bound in the major histocompatibility complex (MHC). To convert this binding event into downstream signaling, the TCR complex contains immunoreceptor tyrosine-based activation motifs (ITAMs) that act as docking sites for the cytoplasmic tyrosine kinase ZAP-70. Unique among antigen receptors, the TCR complex uses 10 ITAMs to transduce peptide-MHC binding to the cell interior. Using synthetic, drug-inducible receptor-ligand pairs, it was found that greater ITAM multiplicity primarily enhanced the efficiency with which ligand binding was converted into an intracellular signal. This manifested as an increase in the fraction of cells that became activated in response to antigen, and a more synchronous initiation of TCR-proximal signaling, rather than direct amplification of the intracellular signals. Exploiting these findings, the potency and selectivity of chimeric antigen receptors targeted against cancer were substantially enhanced by modulating the number of encoded ITAMs.
| Item Type: | Journal Article | ||||||
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Science Signaling | ||||||
| Publisher: | American Association for the Advancement of Science | ||||||
| ISSN: | 1945-0877 | ||||||
| Official Date: | 22 May 2018 | ||||||
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| Volume: | 11 | ||||||
| Number: | 531 | ||||||
| Article Number: | eaan1088 | ||||||
| DOI: | 10.1126/scisignal.aan1088 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||
| RIOXX Funder/Project Grant: |
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