Carbamazepine induces focused T cell responses in resolved Stevens-Johnson syndrome and toxic epidermal necrolysis cases but does not perturb the immunopeptidome for T cell recognition

Mifsud, Nicole A., Illing, Patricia T., Lai, Jeffrey W., Fettke, Heidi, Hensen, Luca, Huang, Ziyi, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522, Vivian, Julian P., Kwan, Patrick and Purcell, Anthony W. 2021. Carbamazepine induces focused T cell responses in resolved Stevens-Johnson syndrome and toxic epidermal necrolysis cases but does not perturb the immunopeptidome for T cell recognition. Frontiers in Immunology 12 , 653710. 10.3389/fimmu.2021.653710

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Abstract

Antiseizure medications (ASMs) are frequently implicated in T cell-mediated drug hypersensitivity reactions and cause skin tropic pathologies that range in severity from mild rashes to life-threatening systemic syndromes. During the acute stages of the more severe manifestations of these reactions, drug responsive proinflammatory CD8+ T cells display classical features of Th1 cytokine production (e.g. IFNγ) and cytolysis (e.g. granzyme B, perforin). These T cells may be found locally at the site of pathology (e.g. blister cells/fluid), as well as systemically (e.g. blood, organs). What is less understood are the long-lived immunological effects of the memory T cell pool following T cell-mediated drug hypersensitivity reactions. In this study, we examine the ASM carbamazepine (CBZ) and the CBZ-reactive memory T cell pool in patients who have a history of either Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) from 3-to-20 years following their initial adverse reaction. We show that in vitro drug restimulation of CBZ-reactive CD8+ T cells results in a proinflammatory profile and produces a mainly focused, yet private, T cell receptor (TCR) usage amongst human leukocyte antigen (HLA)-B*15:02-positive SJS or TEN patients. Additionally, we show that expression of these CBZ-reactive TCRs in a reporter cell line, lacking endogenous αβTCR, recapitulates the features of TCR activation reported for ASM-treated T cell lines/clones, providing a useful tool for further functional validations. Finally, we conduct a comprehensive evaluation of the HLA-B*15:02 immunopeptidome following ASM (or a metabolite) treatment of a HLA-B*15:02-positive B-lymphoblastoid cell line (C1R.B*15:02) and minor perturbation of the peptide repertoire. Collectively, this study shows that the CBZ-reactive T cells characterized require both the drug and HLA-B*15:02 for activation and that reactivation of memory T cells from blood results in a focused private TCR profile in patients with resolved disease.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Frontiers Media
ISSN:	1664-3224
Date of First Compliant Deposit:	17 June 2021
Date of Acceptance:	22 March 2021
Last Modified:	04 May 2023 20:22
URI:	https://orca.cardiff.ac.uk/id/eprint/141960

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