CD4⁺CD25⁺ regulatory T cells suppress contact hypersensitivity reactions by blocking influx of effector T cells into inflamed tissue

Abstract

CD4 + CD25 + regulatory T cells (Treg) exert suppressive functions on effector T cells in vitro and in vivo. However, the exact cellular events that mediate this inhibitory action remain largely unclear. To elucidate these events, we used intravital microscopy in a model of contact hypersensitivity (CHS) and visualized the leukocyte-endothelium interaction at the site of antigen challenge in awake C57BL/6 mice. Injection of Treg i.v. into sensitized mice at the time of local hapten challenge significantly inhibited rolling and adhesion of endogenous leukocytes to the endothelium. A similar inhibition of leukocyte recruitment could be recorded after injection of Treg-derived tissue culture supernatant. Thus, these data indicate that soluble factors may account for the suppressive effects. Accordingly we found that IL-10, but not TGF-b, was produced by Treg upon stimulation and that addition of anti-IL-10 antibodies abrogated the suppressive effects of Treg and tissue culture supernatant in CHS reactions. Moreover, CD4 + CD25 + T cells isolated from IL-10 -/-mice were not able to suppress the immune response induced by hapten treatment in C57BL/6 mice. In conclusion, our data suggest that cytokine-dependent rather than cell-cell contact-dependent mechanisms play a pivotal role in the suppression of CHS reactions by Treg in vivo.

Endogenous Regulatory T Cells Adhere in Inflamed Dermal Vessels via ICAM-1: Association with Regulation of Effector Leukocyte Adhesion

“…Ring et al (42,46) showed that transfer of exogenous CD25 + Tregs resulted in a reduction in leukocyte adhesion in dermal venules at the site of hapten challenge, with evidence supporting a role for Treg-derived IL-10 and adenosine in inhibiting endothelial adhesion molecule expression. However, in these experiments, transferred Tregs were not found in the challenged skin, an observation at odds with previous findings that Treg homing to the skin is required for effective regulation of inflammation (21)(22)(23).…”

“…These altered kinetics suggested that inflammation during the second challenge was being limited by more active immune regulation. Given that Tregs have been shown to be capable of limiting CS responses (42)(43)(44), this raised the possibility that Tregs contribute to the accelerated resolution of inflammation during the second challenge. To understand the contribution of Tregs in this response, we therefore examined the time course of Treg accumulation in the two-challenge CS model.…”

“…We reasoned that using our knowledge of the adhesive mechanisms used by endogenous Tregs, we could interfere with adhesion and recruitment of Tregs and assess the effect on the activation state of the dermal vasculature by examining neutrophil adhesion (42,46). During the first challenge, in mice in which Treg adhesion was blocked by anti-ICAM-1, neutrophil adhesion was not significantly altered (Fig.…”

Imunopatologia da dermatite de contato alérgica

“…108 On the other hand, in vivo models indicate suppression mediated by the action of cytokines, especially IL-10. 109 It is possible that regulatory T cells work in a cooperative system, since it has been shown that Treg cells induce the production of IL-10 in Tr1 cells. 110 These two types of regulatory cells present a wide range of chemokine receptors, such as CCR4 and CCR8, and are attracted by chemokines produced in the late phase of ACD, such as CCL1.…”

CD4⁺CD25⁺ and CD4⁺CD25high regulatory T cells in disseminated and localized forms of allergic contact dermatitis: relation to specific cytokines

“…Adaptive Tregs are induced from native T cells by a specific mode of antigen stimulation, especially in a particular cytokine milieu [16,17] CD25 high ) [14]. The role of Tregs in allergic contact dermatitis has been studied in experimental conditions in vitro or in animal models, but in humans it has been evaluated mainly on patch test reactions [19][20][21][22][23]. This is why the examinations concern only the induction phase or the very early stage of effector phase of ACD and very limited (only one small skin lesion) form of disease.…”