AUTHOR=Mifsud Nicole A. , Illing Patricia T. , Lai Jeffrey W. , Fettke Heidi , Hensen Luca , Huang Ziyi , Rossjohn Jamie , Vivian Julian P. , Kwan Patrick , Purcell Anthony W. 

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.653710

DOI=10.3389/fimmu.2021.653710

ISSN=1664-3224

ABSTRACT=<p>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<sup>+</sup> T cells display classical features of Th1 cytokine production (<italic>e.g.</italic> IFNγ) and cytolysis (<italic>e.g.</italic> granzyme B, perforin). These T cells may be found locally at the site of pathology (<italic>e.g.</italic> blister cells/fluid), as well as systemically (<italic>e.g.</italic> 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 <italic>in vitro</italic> drug restimulation of CBZ-reactive CD8<sup>+</sup> 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 <italic>private</italic> TCR profile in patients with resolved disease.</p>