Diabetes Center at San Diego, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA.
J Autoimmun. 2010 Jun;34(4):445-52. doi: 10.1016/j.jaut.2009.11.010. Epub 2009 Dec 9.
Redirection of immune responses by manipulation of antigen-presenting cells is an emerging strategy for immunosuppressive treatment of autoimmune diseases. In vivo expansion of dendritic cells (DC) by Fms-like tyrosine kinase-3 (Flt3)-Ligand (FL) treatment was shown to delay diabetes onset in the NOD model of autoimmune diabetes. However, we show here that Flt3 stimulation actually accelerates autoimmunity when autoreactive CD8 T cells are detectable in blood prior to treatment. With autoreactive CD8 cells present, the capacity of FL to expand DCs and induce Treg remained intact, but both numbers and the functional response of islet-specific CD8s were boosted. Also, the inhibitory receptor PD-1 on (autoreactive) CD8 T cells and its ligand PD-L1 on Treg were no longer upregulated. These data highlight the need to pre-screen for T cell autoreactivity prior to generalized DC expansion and illustrate how accelerated disease can occur when the intended initiation of regulatory mechanisms is impaired later in diabetogenesis.
通过操纵抗原呈递细胞来重新定向免疫反应是一种新兴的治疗自身免疫性疾病的免疫抑制策略。体内扩增树突状细胞（DC）的 Fms 样酪氨酸激酶-3（Flt3）配体（FL）治疗被证明可以延迟 NOD 自身免疫性糖尿病模型中的糖尿病发作。然而，我们在这里表明，当在治疗前血液中可检测到自身反应性 CD8 T 细胞时，Flt3 刺激实际上会加速自身免疫。在存在自身反应性 CD8 细胞的情况下，FL 扩增 DC 和诱导 Treg 的能力仍然完好，但胰岛特异性 CD8 的数量和功能反应都增强了。此外，（自身反应性）CD8 T 细胞上的抑制受体 PD-1 和 Treg 上的 PD-L1 不再上调。这些数据强调了在广泛的 DC 扩增之前需要预先筛选 T 细胞自身反应性，并说明了当在糖尿病发生过程中后期调节机制的预期启动受到损害时，疾病如何加速发生。
