PXD082505

PXD082505 is an original dataset announced via ProteomeXchange.

Title	Carbamazepine Activates Private Self and Viral Reactive TCRs Through a Drug-Permissive HLA-B Cleft
Description	Carbamazepine (CBZ) can cause severe cutaneous adverse reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis, and is strongly associated with HLA risk alleles. However, HLA genotype alone incompletely predicts clinical risk. Adverse drug reactions depend on drug-peptide-HLA conformation, immunoregulatory cell interactions and the presence of drug-specific TCR clonotypes in susceptible patients. An unresolved question is whether patients that develop a specific drug reaction harbor the same drug-specific TCR (public TCR) or generate patient unique TCRs (private TCR). To address this controversy we expressed four published CBZ-associated TCRs including two public and two private clonotypes, in TCR-null TG40 cells and tested activation using monoallelic 721.221 APCs expressing HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, or HLA-B*58:01(TE→MA), as well as HLA-transgenic/MHC I-deficient murine splenic APCs. T-cell activation was quantified by PD-1, CD69, and 4-1BB, while LC-MS/MS immunopeptidomics/MAPPs was used to assess drug effects on the peptide repertoire. CBZ docking was applied to define drug-peptide-MHC-TCR interactions in a drug reactive peptide specific TCR. Public TCRs showed no CBZ-dependent activation, whereas private TCRs displayed dose-dependent, HLA class I-dependent responses supported by HLAB*15:02 and unexpectedly HLA-B*57:01, but not HLA-B*58:01. Amino acid substitutions to HLA-B*58:01 (T45-E46 to M45-A46) mapped drug presentation to restore CBZ responsiveness without altering HLA expression. CBZ did not detectably induce broad abacavir-like peptide motif alterations but amplified HIV Gag KF11 peptide-driven T cell activation in an allele- andmutation-dependentmanner. Modeling predicted a candidate CBZ accessible region beneath the peptide near HLA Met67, HLA Tyr9, and a conserved CDR3a tyrosine providing a plausible structural rationale for allele and clonotype-dependent activation. These findings support a model in which CBZ potentiates binding of selected peptide-HLA-TCR interfaces governed by HLA cleft architecture and clonotype-level TCR sensitivity. This mechanismexplains why HLA screening alone incompletely predicts CBZ-SJS/ TEN risk and highlights peptide-HLA-TCR functional context as a potential determinant for improved risk assessment and mechanistic drug hypersensitivity testing.
HostingRepository	PRIDE
AnnounceDate	2026-08-18
AnnouncementXML	Submission_2026-08-18_09:29:21.403.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD082505
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	SuJin Hwang
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	cysteinylation (disulfide with free L-cysteine); acetylated residue; monohydroxylated residue; deamidated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2026-08-13 10:26:57	ID requested
⏵ 1	2026-08-18 09:29:21	announced

10.6019/PXD082505;

submitter keyword: HLA-B*57:01, HLA-B*58:01, Stevens-Johnson syndrome, immunopeptidomics, HLA-B*15:02, T-cell receptor, toxic epidermal necrolysis,carbamazepine

Michael Norcross
contact affiliation	Division of Product Quality Research 4, Office of Product Quality Research, Office of Product Quality, Center for Drug Evaluation and Research, U.S. Foodand Drug Administration, Silver Spring, Maryland, USA
contact email	michael.norcross@fda.hhs.gov
lab head
SuJin Hwang
contact affiliation	US Food and Drug Administration
contact email	sujin.hwang@fda.hhs.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD082505
     1. Label: PRIDE project
     2. Name: Carbamazepine Activates Private Self and Viral Reactive TCRs Through a Drug-Permissive HLA-B Cleft