The Use of T Cells in Hazard Characterization of Chemical and Drug Allergens and Integration in Testing Strategies

Abstract

The activation of T lymphocytes expressing the αβ T-cell receptor (TCR) is a crucial event in the development of adaptive immune responses. T lymphocytes circulate throughout the organism and enter sequentially into contact with antigen-presenting cells (APC) displaying on their surface antigenic peptides bound to molecules of the major histocompatibility complex (MHC). The binding of TCR to specific peptide-MHC complexes (pMHC) triggers a cascade of intracellular signaling effectors leading to T-cell cytokine production, proliferation, and/or killing of target cells (Valitutti et al. 2010). However, for chemicals and drugs, the concept of antigenic structures presented to T cells by APC can vary compared to what is described for “classical” antigens. A chemical or a drug is not antigenic on its own because of its small size and it must first bind to a high molecular weight protein to be immunogenic. A stable covalent binding of a chemically reactive drug or chemical to a larger protein or peptide is then immunogenic and can be recognized directly by T cells after undergoing antigen processing of the hapten-carrier complex (hapten hypothesis). The chemical properties of hapten-like drugs are then crucial for the generation of antigenic epitopes and activation of the innate immune system. However, this is only one possibility for T-cell activation by chemicals, and other situations have been also described such as direct binding of chemicals to peptide loaded with HLA molecules, the p-i concept proposing that a drug is able to stimulate T cells directly without forming a hapten in a HLA-dependent manner, and the specific case of transition metals such as nickel forming coordination liaisons with HLA-loaded peptides and the TCR (Vocanson et al. 2009; Yun et al. 2012). These aspects will be addressed in this book by Christine Louis-Dit-Sully and Wolfgang W. A. Schamel in the chapter Activation of the TCR Complex by Small Chemical Compounds and also by H.-U. Weltzien, J.-F. Nicolas, and S. F. Martin in the chapter T Cell Responses to Contact Allergens. Identification of the haptenized peptides presented to T cells from circulating drug-bound proteins such as albumin found in allergic patients using specific methodologies such as mass spectrometry is also a very valuable approach to understand the mechanism underlying drug allergy, and this aspect is covered by C. J. Earnshaw, T. Pecaric-Petkovic, B. K. Park, and D. J. Naisbitt in the chapter T-Cell Responses to Drugs and Drug Metabolites in this book.