IL-12 Instructs Skin Homing of Human Th2 Cells

Abstract

Distinct pattern of homing receptors determines the tissue preference for T cells to exert their effector functions. This homing competence is mostly determined early during T cell activation of naive T cells. In contrast, mechanisms governing the acquisition of particular homing receptors by T cells of the memory phenotype remain enigmatic. Th2 cell-mediated allergic diseases tend to flare during infections despite that these infections prime APCs to produce the prototypic Th1 cell-differentiating cytokine IL-12. In this study, we investigate the effect of IL-12 on the regulation of cutaneous lymphocyte Ag (CLA) on differentiated Th2 cells and consequences of this expression for allergic inflammation. Upon activation with IL-12, CLA− Th2 cells rapidly up-regulated IL-12Rβ2 chain, α(1-3)-fucosyltransferase VII, and CLA molecules. IL-12-mediated CLA expression on Th2 cells was functional because it mediated rolling of these Th2 cells on E-selectin in vitro and migration into human skin grafts in SCID mice. CLA induction occurred immediately after exposure to IL-12 and was independent of IFN-γ expression. In accordance, the transcription factor mediating IFN-γ expression, T-bet, does not directly affect CLA expression. However, CLA expression was further enhanced after IL-12 treatment of T-bet+-transfected Th2 cells in agreement with an increased IL-12 responsiveness of these cells caused by T-bet. The finding that IL-12 conferred skin-homing potential to already differentiated Th2 cells before inducing a switch in their cytokine production profile may explain the observed exacerbation of allergic skin diseases following bacterial infections.

Fucosyltransferase VII‐positive, skin‐homing T cells in the blood and skin lesions of atopic dermatitis patients

“…Unexpected in our study was the observations that the vast majority of T cells found in the epidermis of AD patients expressed both Fuc‐TVII and CLA and that the frequencies were significantly higher than that in psoriasis, which is characterized by Th1 cell infiltration (29). Recent studies (30) and our in vitro ongoing studies demonstrate that this Fuc‐TVII + CLA + phenotype can only be induced by stimulating Th2 cells in the presence of interleukin (IL)‐12 (Takahashi R, unpublished data). Given such a requirement for IL‐12 in the acquisition of this phenotype for Th2 cells, our data suggest that IL‐12 produced by Langerhans cells, keratinocytes and macrophages (31) is a predominant mediator for the generation of this phenotype in AD; in this regard, bacterial (32) and viral infections frequently observed in AD skin would serve to increase this phenotype via increased IL‐12 production.…”

Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4–mediated suppression of IL-10

“…J ALLERGY CLIN IMMUNOL VOLUME nnn, NUMBER nn development of AD inflammation is the initial recruitment of IL-4-producing T H 2 cells to the skin on acute triggering factors, among them exposure to environmental allergens. [29][30][31] However, the switch from acute AD flares to chronic cutaneous inflammation is not understood, and functional human in vivo studies are difficult to perform. Cutaneous colonization or infections with S aureus are found in almost all patients with AD, demonstrating a positive correlation between bacterial density and the severity of AD.…”

Interferon-γ Induces Senescence in Normal Human Melanocytes

“…But the mechanisms that provoke the immune response against autologous melanocytes are still unclear. Since cytokines and the related inflammatory mediators modulate the activation and skin homing of lymphocytes [6], [7], they are the important research objectives for elucidating the onset of autoimmune vitiligo. On the other hand, the discovery of redox imbalance in the vitiligo links the oxidative stress to vitiligo [8]–[10].…”