Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-γ-induced nitric oxide production
Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-γ-induced nitric oxide production
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DOI：
10.4049/jimmunol.175.3.1586
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发表时间：
2005-08-01
影响因子：
4.4
通讯作者：
Okumura, K
中科院分区：
文献类型：
--
作者：
Yamazaki, H;Akiba, H;Okumura, K
PD-1是一种免疫抑制受体，属于CD 28/CTLA-4家族。属于B7家族的B7-H1（PD-L1）和B7-DC（PD-L2）已被鉴定为PD-1的配体。巧合的是，已经报道B7-H1和B7-DC两者共刺激或抑制T细胞增殖和细胞因子产生。为了确定B7-H1和B7-DC在T细胞-APC相互作用中的作用，我们使用抗B7-H1、抗B7-DC和抗PD-1阻断mAb检测了B7-H1和B7-DC对由B细胞、树突状细胞和巨噬细胞激活的CD 4（+）T细胞的贡献。抗B7-H1单抗及其Fab片段可显著抑制抗CD 3刺激的幼稚CD 4（+）T细胞的增殖，但在巨噬细胞存在下可促进IL-2和IFN-γ的产生。抗137-H1单抗对T细胞增殖的抑制作用可被中和性抗IFN-γ单抗所消除。从IFN-γ缺陷型或野生型小鼠的CD 4（+）T细胞和巨噬细胞的共培养显示，CD 4（+）T细胞来源的IFN-γ主要负责抑制CD 4（+）T细胞增殖。抗B7-H1 mAb诱导IFN-γ介导的巨噬细胞产生NO，诱导型NO合成酶抑制剂消除抗B7-H1 mAb对CD 4（+）T细胞增殖的抑制。这些结果表明，抗137-H1单克隆抗体对T细胞增殖的抑制是由于IFN-γ产生的增强，这增加了巨噬细胞的NO产生，表明巨噬细胞上的B7-H1在调节幼稚CD 4（+）T细胞产生IFN-γ和巨噬细胞产生NO中起关键作用。
PD-1 is an immunoinhibitory receptor that belongs to the CD28/CTLA-4 family. B7-H1 (PD-L1) and B7-DC (PD-L2), which belong to the B7 family, have been identified as ligands for PD-1. Paradoxically, it has been reported that both B7-H1 and B7-DC costimulate or inhibit T cell proliferation and cytokine production. To determine the role of B7-H1 and B7-DC in T cell-APC interactions, we examined the contribution of B7-H1 and B7-DC to CD4(+) T cell activation by B cells, dendritic cells, and macrophages using anti-B7-H1, anti-B7-DC, and anti-PD-1 blocking mAbs. Anti-B7-H1 mAb and its Fab markedly inhibited the proliferation of anti-CD3-stimulated naive CD4(+) T cells, but enhanced IL-2 and IFN-gamma production in the presence of macrophages. The inhibition of T cell proliferation by anti-137-Hl mAb was abolished by neutralizing anti-IFN-gamma mAb. Coculture of CD4(+) T cells and macrophages from IFN-gamma-deficient or wild-type mice showed that CD4(+) T cell-derived IFN-gamma was mainly responsible for the inhibition of CD4(+) T cell proliferation. Anti-B7-H1 mAb induced IFN-gamma-mediated production of NO by macrophages, and inducible NO synthase inhibitors abrogated the inhibition of CD4(+) T cell proliferation by anti-B7-H1 mAb. These results indicated that the inhibition of T cell proliferation by anti-137-Hl mAb was due to enhanced IFN-gamma production, which augmented NO production by macrophages, suggesting a critical role for B7-H1 on macrophages in regulating IFN-gamma production by naive CD4(+) T cells and, hence, NO production by macrophages.