{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:24:43Z","timestamp":1787145883715,"version":"build-2736575974"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>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, immuno-regulatory 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2192MA), 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and discussion<\/jats:title>\n                    <jats:p>Public TCRs showed no CBZ-dependent activation, whereas private TCRs displayed dose-dependent, HLA class I-dependent responses supported by HLA-B*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- and mutation-dependent manner. Modeling predicted a candidate CBZ accessible region beneath the peptide near HLA Met67, HLA Tyr9, and a conserved CDR3\u03b1 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 mechanism explains 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1919927","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T12:37:39Z","timestamp":1787143059000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Carbamazepine activates private self and viral reactive TCRs through a drug-permissive HLA-B cleft"],"prefix":"10.3389","volume":"17","author":[{"given":"SuJin","family":"Hwang","sequence":"first","affiliation":[{"name":"Division of Product Quality Research 4, Office of Product Quality Research, Office of Product Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration","place":["Silver Spring, MD, United 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Product Quality Research, Office of Product Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration","place":["Silver Spring, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Gorman","sequence":"additional","affiliation":[{"name":"Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration","place":["Silver Spring, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Puig","sequence":"additional","affiliation":[{"name":"Division of Product Quality Research 4, Office of Product Quality Research, Office of Product Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration","place":["Silver Spring, MD, United 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