Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs
Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs
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DOI：
10.1189/jlb.3a1014-466rr
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发表时间：
2015-06-01
影响因子：
5.5
通讯作者：
Taylor, Andrew W.
中科院分区：
文献类型：
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作者：
Lee, Darren J.;Taylor, Andrew W.
EAU（内源性人自身免疫性葡萄膜炎的小鼠模型）的恢复以脾脏中自身抗原特异性调节性免疫的出现为标志，其保护小鼠免于EAU复发。这种调节性免疫由黑皮质素驱动的抑制性APC介导，该APC呈递自身抗原并使用腺苷通过A2 Ar激活抗原特异性CD 4（+）T细胞。这些细胞在抑制葡萄膜炎方面非常有效，并且它们似乎是可诱导的T细胞。在这项研究中，我们确定了它们是否是诱导型或天然的T细胞，并确定了这些EAU后T细胞功能的依赖机制。对EAU后脾CD 25（+）CD 4（+）T细胞进行NRP-1表达分选，并转移至针对EAU免疫的受体小鼠。分选的NRP-1（-），而不是NRP-1（+），TcR抑制EAU。这些NRP-1（-）T细胞共表达PD-1和PD-L1。用α-MSH处理幼稚APC促进了以CD 73依赖性方式诱导CD 25（+）CD 4（+）T细胞的调节性APC。这些T细胞是PD-L1（+）PD-1（+）NRP-1（-）FOXP 3（+）HELIOS-，当转移到受体小鼠时，抑制EAU。相反，PD-1（-）T细胞不抑制EAU，表明PD-1对于iTlR的抑制活性是必需的。此外，当PD/-1/PD-L1通路被阻断时，这些TcR不抑制效应T细胞。这些结果表明，EAU后的TcR是诱导型TcR，其使用PD-1/PD-L1机制来抑制疾病。
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 alpha-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.