The Roles of Immunoregulatory Networks in Severe Drug Hypersensitivity

Abstract

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

Keywords: Stevens-Johnson Syndrome; contact dermatitis; cosignaling pathways; delayed type hypersensitivity; drug reaction with eosinophilia and systemic symptoms; immune checkpoints; regulatory T cells; toxic epidermal necrolysis.

Figure 1

Immunoregulatory molecules and cytokines implicated in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). CD8+ cytotoxic T lymphocytes (CTLs) play a central role in the pathogenesis of SJS/TEN. Cytokines (including IL-15 and TNF) and costimulatory molecules of APCs can stimulate the CTLs, which in turn produce cytokines, including IFN-γ and IL-15. CTL and NK cell degranulation that induce keratinocyte apoptosis may be mediated, at least partially, by the interaction between CD49/NKG2C and HLA-E. Other players in SJS/TEN include Fas/FasL interactions, T cells and keratinocytes expressing PD-L1, and CD40/CD40L interactions at the dermal-epidermal junction. Ag, antigen; APC, antigen presenting cell; CD40(L), cluster of differentiation 40 (ligand); FasL, Fas ligand; GNLY, granulysin; GzmB, granzyme B; HLA-E, HLA class I histocompatibility antigen, alpha chain E; IFN-γ, interferon gamma; IL-15, Interleukin 15; MHC, major histocompatibility complex; NK cell, natural killer cell; Perf, perforin; PD-L1, programmed death ligand-1; TCR, T cell receptor; TNF, tumor necrosis factor; Treg: regulatory T cell.

Figure 2

Immunoregulatory molecules and cytokines implicated in drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS) and maculopapular exanthema (MPE). Through cell-cell interaction, APCs are thought to activate drug-specific T cells with the aid of OX40 costimulation which prevent T cells from being inhibited by Tregs. Activated Th2 secretes cytokines including IL-4, IL-5, and IL-13, inducing eosinophilia. In addition, eotaxin and TARC produced by keratinocytes and DCs, respectively, promote the local accumulation of harmful eosinophils. Together with the elevated levels of pro-inflammatory cytokines, including IFN-γ, TNF, IL-6, and IL-15, they cause systemic inflammation characterized as DRESS/DIHS. In the case of MPE, the augmented immune responses through the CD40 axis along with the compromised inhibitory mechanisms of both PD-1 and TIM-3 axes were further identified. APC, antigen presenting cell; DC, dendritic cells; Gal-9, galectin-9; GNLY, granulysin; IFN-γ, interferon gamma; IL-4, interleukin 4; IL-5, interleukin 5; IL-6, interleukin 6; IL-13, interleukin 13; IL-15, interleukin 15; MΦ, macrophage; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand-1; TARC, thymus activation-regulated chemokine; TCR, T cell receptor; Th2, T helper 2 cell; TIM-3, T-cell immunoglobulin mucin-3; TNF, tumor necrosis factor; Treg, Regulatory T cell.

Figure 3

Immunoregulatory molecules and cytokines implicated in contact hypersensitivity (CHS). During sensitization, the skin-penetrating hapten is processed by Langerhans cells (LCs) or dermal dendritic cells. GITR-GTRL interactions between keratinocytes and LCs enhance keratinocyte secretion of cytokines, which aid maturation and migration of LCs to the skin-draining lymph node. In the SDLN, in addition to hapten presentation, several costimulatory and coinhibitory interactions, e.g., CD40-CD40L, OX40L-OX40, B7-CD28, and B7-CTLA-4, between the APC and the naïve T cell take place. The hapten-specific effector T cells, predominantly CD8+ cytotoxic T cells, infiltrate the skin and elicit the CHS response upon hapten re-exposure. The presence of Tregs and several coinhibitory receptors on CD8+ T cells and CD8+ Trm cells are associated with decreased CHS response. APC, antigen presenting cell; BTLA, B- and T-lymphocyte attenuator; CD40L, CD40 ligand; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; Gal-9, galectin-9; GITR(L), glucocorticoid induced TNF receptor (ligand); HEVM, herpes virus entry mediator; IL-1β, interleukin-1 beta; LC, Langerhans cell; MHC, major histocompatibility complex; OX40L, OX40 ligand; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand-1; SDLN, skin-draining lymph nodes; TCR, T cell receptor; TIM-3, T-cell immunoglobulin mucin-3; TNF, tumor necrosis factor; Treg, regulatory T cell; Trm, tissue-resident memory T cell.

Figure 4

Regulatory T cells in delayed-type hypersensitivity. Tregs may exert immunosuppressive effect on APCs, effector T cells, and mast cells by the following mechanisms: coinhibitory receptors binding to cognate molecules on dendritic cells, secretion of inhibitory cytokines, e.g., IL-10 and TGF-β, metabolic disruption by depriving IL-2 binding and increasing adenosine binding to effector T cells, and contact-dependent cytolysis by granzyme B secretion. Likewise, cytokines and immunoregulatory molecules also modulate the Treg function. AHR, aryl hydrocarbon receptor; ATP, adenosine triphosphate; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; DC, dendritic cell; IL-2, interleukin 2; IL-7, interleukin 7; IL-10, interleukin 10; IL-15, interleukin 15; IL-33, interleukin 33; LAG-3, lymphocyte-activation gene 3; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; TCR, T cell receptor; TGF-β, transforming growth factor beta; TIGIT, T cell immunoreceptor with Ig and ITIM domains; Treg, regulatory T cell.