Lee Darren J, Taylor Andrew W
Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA.
Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA
J Leukoc Biol. 2015 Jun;97(6):1101-9. doi: 10.1189/jlb.3A1014-466RR. Epub 2015 Apr 15.
The recovery of EAU, a mouse model of endogenous human autoimmune uveitis, is marked with the emergence of autoantigen-specific regulatory immunity in the spleen that protects the mice from recurrence of EAU. This regulatory immunity is mediated by a melanocortin-driven suppressor APC that presents autoantigen and uses adenosine to activate an antigen-specific CD4(+) Tregs through the A2Ar. These cells are highly effective in suppressing uveitis, and they appear to be inducible Tregs. In this study, we determined whether they are inducible or natural Tregs and identified the dependent mechanism for the function of these post-EAU Tregs. The post-EAU spleen CD25(+)CD4(+) T cells were sorted for NRP-1 expression and transferred to recipient mice immunized for EAU. The sorted NRP-1(-), but not the NRP-1(+), Tregs suppressed EAU. These NRP-1(-) Tregs coexpress PD-1 and PD-L1. Treatment of naive APCs with α-MSH promoted a regulatory APC that induced CD25(+) CD4(+) Tregs in a CD73-dependent manner. These Tregs were PD-L1(+) PD-1(+) NRP-1(-) FOXP3(+) HELIOS(-) and suppressed EAU when transferred to recipient mice. In contrast, PD-1(-) T cells did not suppress EAU, indicating that PD-1 is necessary for the suppressive activity of iTregs. Moreover, these Tregs did not suppress effector T cells when the PD/-1/PD-L1 pathway was blocked. These results demonstrate that post-EAU Tregs are inducible Tregs, which use a PD-1/PD-L1 mechanism to suppress disease.
实验性自身免疫性葡萄膜炎（EAU）是一种内源性人类自身免疫性葡萄膜炎的小鼠模型，其恢复表现为脾脏中出现自身抗原特异性调节性免疫，可保护小鼠免于EAU复发。这种调节性免疫由黑素皮质素驱动的抑制性抗原呈递细胞（APC）介导，该细胞呈递自身抗原，并利用腺苷通过A2Ar激活抗原特异性CD4(+)调节性T细胞（Tregs）。这些细胞在抑制葡萄膜炎方面非常有效，并且它们似乎是诱导性Tregs。在本研究中，我们确定它们是诱导性还是天然Tregs，并确定这些EAU后Tregs功能的依赖机制。对EAU后脾脏CD25(+)CD4(+) T细胞进行分选以检测神经纤毛蛋白-1（NRP-1）表达，并将其转移至免疫诱导EAU的受体小鼠。分选得到的NRP-1(-)而非NRP-1(+) Tregs可抑制EAU。这些NRP-1(-) Tregs共表达程序性死亡受体1（PD-1）和程序性死亡配体1（PD-L1）。用α-促黑素（α-MSH）处理幼稚APC可促进一种调节性APC，其以CD73依赖的方式诱导CD25(+) CD4(+) Tregs。这些Tregs为PD-L1(+) PD-1(+) NRP-1(-)叉头框蛋白3（FOXP3(+)）太阳神蛋白（HELIOS(-)），转移至受体小鼠后可抑制EAU。相反，PD-1(-) T细胞不能抑制EAU，表明PD-1对诱导性Tregs的抑制活性是必需的。此外，当PD/-1/PD-L1途径被阻断时，这些Tregs不能抑制效应T细胞。这些结果表明，EAU后Tregs是诱导性Tregs，其利用PD-1/PD-L1机制抑制疾病。
