Skin Resident Memory T Cells May Play Critical Role in Delayed-Type Drug Hypersensitivity Reactions

Abstract

Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (T_RM) are a unique T cell population potentially well situated to act as key mediators in disease pathogenesis, but significant obstacles to defining, identifying, and testing T_RM in dtDHR preclude definitive conclusions at this time. Deeper mechanistic interrogation to address these unanswered questions is necessary, as involvement of T_RM in disease has significant implications for prediction, diagnosis, and treatment of disease.

Keywords: Stevens-Johnson syndrome; adverse drug reactions; delayed-type drug hypersensitivity reactions; drug reaction with eosinophil and systemic symptoms; fixed drug eruption; maculopapular exanthem; tissue-resident memory T cells; toxic epidermal necrolysis.

Figure 1

Possible mechanisms by which drug-reactive T_RM could be generated in skin. (A) Drug/drug altered peptide repertoire is presented to drug-reactive T cells and concurrent viral infection/reactivation provides sufficient co-stimulation to break T cell tolerance to drug: 1. Inflammatory mediators secondary to infection stimulate dendritic cells. 2. Activated dendritic cells in skin draining lymph nodes present drug/drug altered peptide repertoire to naïve drug-reactive T cells and provide ample co-stimulation resulting in T cell priming. 3. Primed T cells proliferate and differentiate into effector cells, 4. migrate to skin, and 5. mediate damage as a primary immune response. 6. Despite resolution of inflammation, drug-reactive T_RM remain in skin, poised to mediate repeat dtDHR upon re-exposure to drug. Alternatively, factors other than viral infection, for example altered drug metabolism or reduced clearance, could potentially lead to T cell activation (not shown). (B) Drug-reactive T cells are cross-reactive to viral epitopes: 1. Virus-specific T_RM accumulate in skin as a consequence of prior infection. 2. These virus-reactive T cells are capable of recognizing (cross-reacting to) drug/drug altered peptide repertoire presented by MHC on the surface of skin dendritic cells, macrophages and/or keratinocytes resulting in T_RM stimulation. 3. The stimulated T_RM produce pro-inflammatory molecules inducing DRESS, or potentially other dtDHR.