In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Abstract

Contact hypersensitivity (CHS) of murine skin serves as a model of allergic contact dermatitis. Hapten-specific CD8 T cells and neutrophils represent the major effector cells driving this inflammatory reaction whereas Foxp3+ regulatory T cells (Tregs) control the severity of inflammation. However, whether in vivo expansion of endogenous Tregs can downregulate CHS-mediated inflammation remains to be elucidated. In this study, we addressed this issue by using injection of an IL-2/anti–IL-2 mAb JES6-1 complex (IL-2/JES6-1) as a means of Treg induction in 2,4,6-trinitrochlorobenzene–induced CHS. IL-2/JES6-1 injection before or after hapten sensitization led to a considerable reduction of skin inflammation, even when rechallenged up to 3 wk after the last treatment. Conversely, Treg depletion re-established the CHS response in IL-2/JES6-1–treated mice. IL-2/JES6-1 injection resulted in increased frequencies of natural and peripheral Tregs in spleen and draining lymph nodes (LNs), elevated IL-10 and TGF-β production by CD4 T cells, reduced CD86 expression by dendritic cells, and led to lower numbers of hapten-specific IFN-γ–producing CD8 T effector cells in LNs. Neutrophil and CD8 T cell infiltration was reduced in inflamed ear tissue, whereas CTLA-4+Foxp3+ Treg frequencies were augmented. Adoptive transfer of LN cells of sensitized mice into recipients treated with IL-2/JES6-1 showed impaired CHS. Our results show that in vivo Treg expansion results in a prolonged CHS suppression, a sustained reduction of hapten-specific CD8 T cells, and a decrease in effector cell influx in inflamed tissue.

Immune dysregulation increases the incidence of delayed‐type drug hypersensitivity reactions

“…Gomez de Aguero et al reported that Langerhans cells (cutaneous dendritic cells) are critical in the regulatory process through inducing the depletion of antigen‐responsive T cells and by activating FOXP3 + Tregs. Furthermore, in vivo expansion of Treg populations has been shown to induce long‐term suppression of contact hypersensitivity . In humans, Cavani et al have reported that CD25 + regulatory T cells maintain tolerance to the contact metal allergen nickel in nonhypersensitive individuals.…”

Recent advances in understanding and managing contact dermatitis

“…El Beidaq et al . demonstrated that tolerance to CHS mediated by TNCB can be enforced by injection of an IL-2/anti-IL-2 antibody reagent, IL-2/JES6-1 58 . This treatment, when given before or even after sensitization, established a state of tolerance by CTLA4 + Foxp3 + Treg expansion that was still evident upon re-challenge with contact allergen even 3 weeks after the last injection.…”

Genetic variation in the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway affects contact hypersensitivity responses

“…Allergic contact dermatitis (ACD) is a T-cell-mediated delayed hypersensitivity reaction characterized by the occurrence of inflammatory skin lesions following contact with a particular allergen. 1 Nonprotein allergens, or haptens, capable of eliciting contact dermatitis include a wide range of substances encountered within occupational or domestic settings. 2 ACD has a reported median prevalence of approximately 20% across Europe and North America and is continuing to increase with limited therapeutic options addressing its burden.…”

“…5 In this study, we used the CC to investigate the genetic factors underlying CHS, the murine model of ACD in which hapten sensitization and subsequent immune challenge can be fully controlled and standardized. 1,2 We assessed CHS in 38 strains of CC mice by measuring the increase in ear thickness at various time points after a single standardized oxazalone challenge (see this article's Methods section in the Online Repository at www.jacionline.org). At each time point, there were marked differences in response between CC strains in both the acute response to immune challenge and postchallenge recovery (see Results and Discussion sections and Fig E1 in this article's Online Repository at www.jacionline.org).…”