Laboratory CNRS UPR3572 Immunology, Immunopathology and Therapeutic Chemistry (I2CT) / LabEx Medalis, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg, Strasbourg, France.
Allergy. 2021 Jul;76(7):2044-2056. doi: 10.1111/all.14718. Epub 2021 Jan 27.
Immune modulation by vitamin D3 through dendritic cells (DCs) remains controversial. Human DCs exposed in vitro counteract type-1 T-helper (Th1) differentiation and induce regulatory T cells. However, cutaneous application on mice promotes Th2-driven inflammation resembling atopic dermatitis and relying on thymic stromal lymphopoietin (TSLP) from keratinocytes and T-cell orientation by TSLP-stimulated skin DCs. We studied the effects of vitamin D3 in human skin, focusing on TSLP production and the role of skin DCs in T-cell differentiation.
Human healthy skin explants were exposed in vitro to vitamin D3 analogs. Migrating DCs were analyzed and TSLP quantified in the supernatant. Allogeneic naïve CD4+ T cells were cocultured with DCs to assess their proliferation and cytokine production.
Vitamin D3 induced skin DCs to differentiate Th2 cells producing IL-4 and IL-13. Vitamin D3 triggered TSLP release in ~30% of skin explants, correlating with IL-13 detection in Th2 cells. In these donors, blocking TSLP receptor during skin explant cultures abrogated IL-13 production, yet IL-4+ Th2 cells were unaffected. Among skin DCs emerged CD14+ cells that had responded directly to vitamin D3 and differed from classical CD14+ dermal emigrants. Vitamin D3-elicited CD14+ DCs sufficed to promote IL-4+ Th2 cells in a TSLP-independent manner.
Vitamin D3, despite inducing TSLP in some donors, had a direct influence on skin DCs, affecting their phenotype and ability to drive Th2 responses independently of TSLP. Our findings pave the way toward in vitro systems that accurately model human cutaneous Th2 responses, notably involved in atopic dermatitis.
维生素 D3 通过树突状细胞 (DC) 对免疫的调节作用仍存在争议。体外暴露的人 DC 可拮抗 1 型 T 辅助 (Th1) 分化并诱导调节性 T 细胞。然而，在小鼠皮肤上应用维生素 D3 会促进 Th2 驱动的炎症，类似于特应性皮炎，并且依赖于角质形成细胞的胸腺基质淋巴细胞生成素 (TSLP) 和 TSLP 刺激的皮肤 DC 对 T 细胞的定向。我们研究了维生素 D3 在人体皮肤中的作用，重点研究 TSLP 的产生以及皮肤 DC 在 T 细胞分化中的作用。
体外将人健康皮肤标本暴露于维生素 D3 类似物中。分析迁移的 DC 并定量上清液中的 TSLP。将同种异体幼稚 CD4+T 细胞与 DC 共培养，以评估其增殖和细胞因子产生。
维生素 D3 诱导皮肤 DC 分化为产生 IL-4 和 IL-13 的 Th2 细胞。维生素 D3 以~30%的皮肤标本触发 TSLP 释放，与 Th2 细胞中 IL-13 的检测相关。在这些供体中，在皮肤标本培养期间阻断 TSLP 受体可阻断 IL-13 的产生，但对 IL-4+Th2 细胞没有影响。在皮肤 DC 中出现了直接对维生素 D3 作出反应的 CD14+细胞，与经典的 CD14+真皮迁出细胞不同。维生素 D3 诱导的 CD14+DC 足以在 TSLP 非依赖的方式下促进 IL-4+Th2 细胞。
尽管维生素 D3 在一些供体中诱导 TSLP，但它对皮肤 DC 有直接影响，影响其表型和独立于 TSLP 驱动 Th2 反应的能力。我们的研究结果为体外系统奠定了基础，这些系统可准确模拟人类皮肤 Th2 反应，特别是在特应性皮炎中涉及的反应。
