Abacavir inhibits but does not cause self-reactivity to HLA-B*57:01-restricted EBV specific T cell receptors
Year: 2022
Type: article
Abstract: Pre-existing pathogen-specific memory T cell responses can contribute to multiple adverse outcomes including autoimmunity and drug hypersensitivity. How the specificity of the T cell receptor (TCR) is subverted or seconded in many of these diseases remains unclear. Here, we apply abacavir hypersensitivity (AHS) as a model to address this question because the disease is linked to memory T cell responses and the HLA risk allele, HLA-B*57:01, and the initiating insult, abacavir, are known. To investigate the role of pathogen-specific TCR specificity in mediating AHS we performed a genome-wide screen for HLA-B*57:01 restricted T cell responses to Epstein-Barr virus (EBV), one of the most prevalent human pathogens. T cell epitope mapping revealed HLA-B*57:01 restricted responses to 17 EBV open reading frames and identified an epitope encoded by EBNA3C. Using these data, we cloned the dominant TCR for EBNA3C and a previously defined epitope within EBNA3B. TCR specificity to each epitope was confirmed, however, cloned TCRs did not cross-react with abacavir plus self-peptide. Nevertheless, abacavir inhibited TCR interactions with their cognate ligands, demonstrating that TCR specificity may be subverted by a drug molecule. These results provide an experimental road map for future studies addressing the heterologous immune responses of TCRs including T cell mediated adverse drug reactions.
Source: Communications Biology
Institutions: Murdoch University, The Kids Research Institute Australia, Vanderbilt University Medical Center, University of Washington, Fred Hutch Cancer Center, Benaroya Research Institute, La Jolla Institute for Immunology, Brigham and Women's Hospital, Harvard University, The University of Western Australia, Institute for Respiratory Health
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funders: Vanderbilt University, University of Washington, Vanderbilt University Medical Center, Murdoch University, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1188586094, G1721873508, G1991070941, G2508017656, G265873141, Improving Prediction of Drug Action, G4198746417, G4512884381, G5126645345, Cutaneous pathogen-specific tissue resident memory T cells in human aging, Stevens-Johnson syndrome/toxic epidermal necrolysis 2021: Collaboration, Innovation and Community, Genetic risk and long-term outcomes associated with Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in survivors, G6771029017, G6900366626, Single Cell definition of pathogenic T cells in Drug-induced Stevens-Johnson-Syndrome/Toxic epidermal necrolysis, Tissue specific T cells mediate drug hypersensitivity, G891294514, Tennessee Center for AIDS Research (TN-CFAR), G9000113402, Training in Cardiovascular Physiology and Pharmacology, Immune Tolerance Network, UCSD Future Faculty of Cardiovascular Sciences (FOCUS), Immune-mediated adverse drug reactions to HIV and TB treatments in South Africa: predict, prevent and improve long-term outcomes (IMARI SA study), NATIENS: A Phase III Randomized Double Blinded Study to Determine the Mechanisms and Optimal Management of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
OpenAlex ID: W4212824712