In Vitro Monitoring of Human T Cell Responses to Skin Sensitizing Chemicals—A Systematic Review

Abstract

Background: Chemical allergies are T cell-mediated diseases that often manifest in the skin as allergic contact dermatitis (ACD). To prevent ACD on a public health scale and avoid elicitation reactions at the individual patient level, predictive and diagnostic tests, respectively, are indispensable. Currently, there is no validated in vitro T cell assay available. The main bottlenecks concern the inefficient generation of T cell epitopes and the detection of rare antigen-specific T cells. Methods: Here, we systematically review original experimental research papers describing T cell activation to chemical skin sensitizers. We focus our search on studies published in the PubMed and Scopus databases on non-metallic allergens in the last 20 years. Results: We identified 37 papers, among them 32 (86%) describing antigen-specific human T cell activation to 31 different chemical allergens. The remaining studies measured the general effects of chemical allergens on T cell function (five studies, 14%). Most antigen-specific studies used peripheral blood mononuclear cells (PBMC) as antigen-presenting cells (APC, 75%) and interrogated the blood T cell pool (91%). Depending on the individual chemical properties, T cell epitopes were generated either by direct administration into the culture medium (72%), separate modification of autologous APC (29%) or by use of hapten-modified model proteins (13%). Read-outs were mainly based on proliferation (91%), often combined with cytokine secretion (53%). The analysis of T cell clones offers additional opportunities to elucidate the mechanisms of epitope formation and cross-reactivity (13%). The best researched allergen was p-phenylenediamine (PPD, 12 studies, 38%). For this and some other allergens, stronger immune responses were observed in some allergic patients (15/31 chemicals, 48%), illustrating the in vivo relevance of the identified T cells while detection limits remain challenging in many cases. Interpretation: Our results illustrate current hardships and possible solutions to monitoring T cell responses to individual chemical skin sensitizers. The provided data can guide the further development of T cell assays to unfold their full predictive and diagnostic potential, including cross-reactivity assessments.

Frequencies and TCR Repertoires of Human 2,4,6-Trinitrobenzenesulfonic Acid-specific T Cells

“…So far, mainly interactions of chemicals with peptides presented by MHC proteins have been studied ( Aparicio-Soto et al, 2021 ). Interactions with TCR residues remain unexplored although they have been theoretically addressed as “p-i TCR” concept ( Pichler, 2019 ).…”

Unique and common TCR repertoire features of Ni2+‐, Co2+‐, and Pd2+‐specific human CD154 + CD4+ T cells

“…To date, optimal metal salt concentrations for the in vitro distinction of allergic and non-allergic individuals have not been established. 16,67,69 Relatively high metal salt concentrations likely capture the complete reactive T cell pool but may activate T cells without in vivo relevance. So far, lower metal ion concentrations have not been associated with improved nickel allergy detection.…”

Oral prednisone regulates human skin T cells in delayed‐type hypersensitivity reaction elicited by diphencyprone

“…It has been reported that as many as 20% of the European population is allergic to at least one chemical. [1][2][3] ACD is characterized by delayed-type hypersensitivity (DTH) reactions, also called Type IV reactions. DTH reactions can result upon exposure to various agents.…”

“…Allergic contact dermatitis (ACD) represents an important occupational health burden. It has been reported that as many as 20% of the European population is allergic to at least one chemical 1–3 . ACD is characterized by delayed‐type hypersensitivity (DTH) reactions, also called Type IV reactions.…”