Department of Internal Medicine and DENOTHE Center, University of Florence, 50134 Firenze, Italy.
Immunity. 2012 Feb 24;36(2):201-14. doi: 10.1016/j.immuni.2011.12.013. Epub 2012 Feb 9.
The reason why CD4(+) T helper 17 (Th17) cells, despite their well-known pathogenic role in chronic inflammatory disorders, are very rare in the inflammatory sites remains unclear. We demonstrate that human Th17 cells exhibit low ability to proliferate and to produce the T cell growth factor interleukin-2 (IL-2), in response to combined CD3 and CD28 stimulation. This was due to the upregulated expression of IL-4-induced gene 1 (IL4I1) mRNA, a secreted L-phenylalanine oxidase, which associated with a decrease in CD3ζ chain expression and consequent abnormalities in the molecular pathway that allows IL-2 production and cell proliferation. High IL4I1 mRNA expression was detectable in Th17 cell precursors and was strictly dependent on Th17 cell master gene, the retinoid acid related orphan receptor (RORC). Th17 cells also exhibited RORC-dependent CD28 hyperexpression and the ability to produce IL-17A after CD28 stimulation without CD3 triggering. Our findings suggest that the rarity of human Th17 cells in inflamed tissues results from RORC-dependent mechanisms limiting their expansion.
CD4(+) T 辅助 17（Th17）细胞尽管在慢性炎症性疾病中具有众所周知的致病性作用，但在炎症部位非常罕见，其原因尚不清楚。我们证明，人 Th17 细胞在受到 CD3 和 CD28 联合刺激时，增殖能力和产生 T 细胞生长因子白细胞介素-2（IL-2）的能力很低。这是由于 IL-4 诱导基因 1（IL4I1）mRNA 的表达上调，这是一种分泌的 L-苯丙氨酸氧化酶，与 CD3ζ 链表达的减少以及允许 IL-2 产生和细胞增殖的分子途径的异常有关。在 Th17 细胞前体中可检测到高 IL4I1 mRNA 表达，并且严格依赖于 Th17 细胞主基因，维甲酸相关孤儿受体（RORC）。Th17 细胞还表现出 RORC 依赖性的 CD28 过度表达，并且在没有 CD3 触发的情况下，在 CD28 刺激后能够产生 IL-17A。我们的研究结果表明，人 Th17 细胞在炎症组织中罕见的原因是 RORC 依赖性机制限制了它们的扩增。
