O'Sullivan Brendan J, Thomas Helen E, Pai Saparna, Santamaria Pere, Iwakura Yoichiro, Steptoe Raymond J, Kay Thomas W H, Thomas Ranjeny
Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
J Immunol. 2006 Jun 15;176(12):7278-87. doi: 10.4049/jimmunol.176.12.7278.
IL-1 is a key proinflammatory driver of several autoimmune diseases including juvenile inflammatory arthritis, diseases with mutations in the NALP/cryopyrin complex and Crohn's disease, and is genetically or clinically associated with many others. IL-1 is a pleiotropic proinflammatory cytokine; however the mechanisms by which increased IL-1 signaling promotes autoreactive T cell activity are not clear. Here we show that autoimmune-prone NOD and IL-1 receptor antagonist-deficient C57BL/6 mice both produce high levels of IL-1, which drives autoreactive effector cell expansion. IL-1beta drives proliferation and cytokine production by CD4(+)CD25(+)FoxP3(-) effector/memory T cells, attenuates CD4(+)CD25(+)FoxP3(+) regulatory T cell function, and allows escape of CD4(+)CD25(-) autoreactive effectors from suppression. Thus, inflammation or constitutive overexpression of IL-1beta in a genetically predisposed host can promote autoreactive effector T cell expansion and function, which attenuates the ability of regulatory T cells to maintain tolerance to self.
白细胞介素-1（IL-1）是多种自身免疫性疾病的关键促炎驱动因子，包括青少年特发性关节炎、NALP/冷吡啉复合物发生突变的疾病以及克罗恩病，并且在基因或临床上与许多其他疾病相关。IL-1是一种多效性促炎细胞因子；然而，IL-1信号增强促进自身反应性T细胞活性的机制尚不清楚。在此我们表明，易患自身免疫性疾病的非肥胖糖尿病（NOD）小鼠和缺乏白细胞介素-1受体拮抗剂的C57BL/6小鼠均产生高水平的IL-1，其驱动自身反应性效应细胞扩增。白细胞介素-1β（IL-1β）可驱动CD4(+)CD25(+)FoxP3(-)效应/记忆T细胞增殖并产生细胞因子，减弱CD4(+)CD25(+)FoxP3(+)调节性T细胞功能，并使CD4(+)CD25(-)自身反应性效应细胞逃脱抑制。因此，在遗传易感性宿主中，IL-1β的炎症或组成性过表达可促进自身反应性效应T细胞扩增和功能，这会减弱调节性T细胞维持自身耐受性的能力。
