Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase
Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase
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DOI：
10.1172/jci31911
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Munn, David H.
中科院分区：
文献类型：
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作者：
Sharma, Madhav D.;Baban, Babak;Munn, David H.
在小鼠肿瘤清除的LNS中，少量的浆细胞样树突状细胞(PDC)可以表达免疫调节酶吲哚胺2，3-双加氧酶(IDO)。我们发现这些IDO+pDC可以直接激活静息的CD4(+)CD25(+)Foxp3(+)树突状细胞，以达到有效的抑制活性。在体内，从肿瘤引流的淋巴结中分离出的Tregs在体外立即被结构性地激活和抑制抗原特异性T细胞。在体外，来自肿瘤引流的LNS的IDO+pDC可以快速激活非荷瘤宿主的静息Tregs，而不需要丝裂原或外源抗CD3交联剂。IDO+pDC对Treg的激活受到MHC的限制，需要Tregs中完整的氨基酸反应GCN2通路，并被CTLA4阻断。经IDO激活的Tregs可显著上调靶DC上PD-L1和PD-L2的表达，其抑制靶T细胞增殖的能力可被抗程序性细胞死亡1/PD-L(PD-1/PD-L)通路的抗体所阻断。相反，抗CD3交联剂激活的Treg不会引起PD-LS的上调，并且这些细胞的抑制不会通过阻断PD-1/PD-L通路而受到影响。从体内肿瘤引流的淋巴结中分离到的Tregs具有很强的PD-1/PD-L介导的抑制作用，当肿瘤生长在IDO缺乏的宿主中时，这种抑制作用被选择性地丧失。我们假设IDO+PDCs通过Tregs的结构性激活在肿瘤引流的LNS内创造了一个深刻的抑制微环境。
A small population of plasmacytoid DCs (pDCs) in mouse tumor-draining LNs can express the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO). We show that these IDO+ pDCs directly activate resting CD4(+)CD25(+)Foxp3(+) Tregs for potent suppressor activity. In vivo, Tregs isolated from tumor-draining LNs were constitutively activated and suppressed antigen-specific T cells immediately ex vivo. In vitro, IDO+ pDCs from tumor-draining LNs rapidly activated resting Tregs from non-tumor-bearing hosts without the need for mitogen or exogenous anti-CD3 crosslinking. Treg activation by IDO+ pDCs was MHC restricted, required an intact amino acid-responsive GCN2 pathway in the Tregs, and was prevented by CTLA4 blockade. Tregs; activated by IDO markedly upregulated programmed cell death 1 ligand 1 (PD-L1) and PD-L2 expression on target DCs, and the ability of Tregs to suppress target T cell proliferation was abrogated by antibodies against the programmed cell death 1/PD-L (PD-1/PD-L) pathway. In contrast, Tregs activated by anti-CD3 crosslinking did not cause upregulation of PD-Ls , and suppression by these cells was unaffected by blocking the PD-1/PD-L pathway. Tregs isolated from tumor-draining LNs in vivo showed potent PD-1/PD-L-mediated suppression, which was selectively lost when tumors were grown in IDO-deficient hosts. We hypothesize that IDO+ pDCs create a profoundly suppressive microenvironment within tumor-draining LNs via constitutive activation of Tregs.