The complexity of T cell–mediated penicillin hypersensitivity reactions

Penicillin refers to a group of beta‐lactam antibiotics that are the first‐line treatment for a range of infections. However, they also possess the ability to form novel antigens, or neoantigens, through haptenation of proteins and can stimulate a range of immune‐mediated adverse reactions—collectively known as drug hypersensitivity reactions (DHRs). IgE‐mediated reactions towards these neoantigens are well studied; however, IgE‐independent reactions are less well understood. These reactions usually manifest in a delayed manner as different forms of cutaneous eruptions or liver injury consistent with priming of an immune response. Ex vivo studies have confirmed the infiltration of T cells into the site of inflammation, and the subsets of T cells involved appear dependent on the nature of the reaction. Here, we review the evidence that has led to our current understanding of these immune‐mediated reactions, discussing the nature of the lesional T cells, the characterization of drug‐responsive T cells isolated from patient blood, and the potential mechanisms by which penicillins enter the antigen processing and presentation pathway to stimulate these deleterious responses. Thus, we highlight the need for a more comprehensive understanding of the underlying genetic and molecular basis of penicillin‐induced DHRs.