Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
Cell Rep. 2018 Mar 6;22(10):2642-2653. doi: 10.1016/j.celrep.2018.02.044.
Th17 cells drive autoimmune disease but also control commensal microbes. A common link among antigens from self-proteins or commensal microbiota is relatively low activation of T cell receptor (TCR) and costimulation signaling. Indeed, strong TCR/CD28 stimulation suppressed Th17 cell differentiation from human naive T cells, but not effector/memory cells. CD28 suppressed the classical Th17 transcriptional program, while inducing known Th17 regulators, and acted through an Akt-dependent mechanism. Th17 cells differentiated without CD28 were not anergic: they showed robust proliferation and maintained Th17 cytokine production following restimulation. Interleukin (IL)-23 and IL-1β promoted glucose uptake and increased glycolysis. Although modestly increased compared to CD28 costimulation, glycolysis was necessary to support Th17 differentiation, indicating that cytokine-mediated metabolic shifts were sufficient to obviate the classical requirement for CD28 in Th17 differentiation. Together, these data propose that, in humans, strength of TCR/CD28/Akt activation serves as a rheostat tuning the magnitude of Th17 development driven by IL-23 and IL-1β.
Th17 细胞可驱动自身免疫性疾病，但也可控制共生微生物。自身蛋白或共生微生物菌群中的抗原之间的一个共同联系是 T 细胞受体（TCR）和共刺激信号的相对低激活。事实上，强烈的 TCR/CD28 刺激抑制了人幼稚 T 细胞向 Th17 细胞的分化，但不能抑制效应/记忆细胞。CD28 抑制了经典的 Th17 转录程序，同时诱导已知的 Th17 调节因子，并通过 Akt 依赖性机制发挥作用。没有 CD28 分化的 Th17 细胞不会失能：它们在重新刺激后表现出强烈的增殖并维持 Th17 细胞因子的产生。白细胞介素（IL）-23 和 IL-1β 促进葡萄糖摄取并增加糖酵解。与 CD28 共刺激相比，虽然略有增加，但糖酵解是支持 Th17 分化所必需的，这表明细胞因子介导的代谢转变足以避免 CD28 在 Th17 分化中的经典要求。总之，这些数据表明，在人类中，TCR/CD28/Akt 激活的强度可作为调节由 IL-23 和 IL-1β 驱动的 Th17 发育程度的变阻器。
