Kryczek Ilona, Bruce Allen T, Gudjonsson Johann E, Johnston Andrew, Aphale Abhishek, Vatan Linhua, Szeliga Wojciech, Wang Yin, Liu Yan, Welling Theodore H, Elder James T, Zou Weiping
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
J Immunol. 2008 Oct 1;181(7):4733-41. doi: 10.4049/jimmunol.181.7.4733.
Th1 and Th17 T cells are often colocalized in pathological environments, yet Th1-derived IFN-gamma inhibits Th17 cell development in vitro. We explored the physiologic basis of this paradox in humans. In this study, we demonstrate increased the number of CD4(+) and CD8(+) IL-17(+) T cells in skin lesions of psoriasis. Furthermore, we show that myeloid APCs potently support induction of IL-17(+) T cells, and that this activity is greatly increased in psoriasis. We tested stimuli that might account for this activity. Th1 cells and IFN-gamma are increased in psoriatic blood and lesional skin. We show that IFN-gamma programs myeloid APCs to induce human IL-17(+) T cells via IL-1 and IL-23. IFN-gamma also stimulates APC production of CCL20, supporting migration of IL-17(+) T cells, and synergizes with IL-17 in the production of human beta-defensin 2, an antimicrobial and chemotactic protein highly overexpressed by psoriatic keratinocytes. This study reveals a novel mechanistic interaction between Th1 and IL-17(+) T cells, challenges the view that Th1 cells suppress Th17 development through IFN-gamma, and suggests that Th1 and IL-17(+) T cells may collaboratively contribute to human autoimmune diseases.
Th1和Th17 T细胞在病理环境中常共定位，但Th1衍生的干扰素-γ在体外抑制Th17细胞发育。我们探究了人类中这一矛盾现象的生理基础。在本研究中，我们证明银屑病皮肤病变中CD4(+)和CD8(+) IL-17(+) T细胞数量增加。此外，我们表明髓样抗原呈递细胞有力地支持IL-17(+) T细胞的诱导，且这种活性在银屑病中大幅增加。我们测试了可能解释这种活性的刺激因素。银屑病血液和皮损中Th1细胞和干扰素-γ增加。我们表明干扰素-γ使髓样抗原呈递细胞编程，通过IL-1和IL-23诱导人IL-17(+) T细胞。干扰素-γ还刺激抗原呈递细胞产生CCL20，支持IL-17(+) T细胞迁移，并在人β-防御素2的产生中与IL-17协同作用，人β-防御素2是一种抗菌和趋化蛋白，在银屑病角质形成细胞中高度过表达。本研究揭示了Th1和IL-17(+) T细胞之间一种新的机制性相互作用，挑战了Th1细胞通过干扰素-γ抑制Th17发育的观点，并表明Th1和IL-17(+) T细胞可能共同促成人类自身免疫性疾病。
