Differential effects of IL-12 receptor blockade with IL-12 p40 homodimer on the induction of CD4+ and CD8+ IFN-gamma-producing cells.
Differential effects of IL-12 receptor blockade with IL-12 p40 homodimer on the induction of CD4+ and CD8+ IFN-gamma-producing cells.
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DOI：
10.4049/jimmunol.158.2.643
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发表时间：
1997-01
影响因子：
4.4
通讯作者：
J. Piccotti;S. Chan;Kewang Li;E. Eichwald;D. Bishop
中科院分区：
文献类型：
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作者：
J. Piccotti;S. Chan;Kewang Li;E. Eichwald;D. Bishop
IL-12 在调节 Th1/Th2 平衡中的作用部分归因于该细胞因子能够诱导 NK 和 Th1 细胞产生 IFNγ，从而促进 Th1 并抑制 Th2 发育。在本研究中，通过向初级 MLC 中添加中和性抗 IL-12 Ab 或 IL-12 受体拮抗剂 p40 同二聚体来评估同种异体抗原反应性 Th1 发育中对 IL-12 的需求。通过测量同种异体抗原再刺激后 IFN-γ 的产生来评估所得细胞群的 Th1 发育。虽然向初级 MLC 添加抗 IL-12 Ab 不会影响随后的细胞因子产生，但添加 p40 同二聚体显着增强而不是降低 Th1 发育。为了确定哪个 T 细胞群响应 p40 同二聚体产生了更高水平的 IFN-γ，从 MLC 中去除了 CD4+ 或 CD8+ T 细胞。虽然 p40 同二聚体抑制特定的 CD4+ Th1 发育，但它增强了 CD8+ T 细胞的 IFN-γ 产生。为了测试这些发现的体内相关性，用 p40 同二聚体、抗 CD8 mAb 或同时用 p40 同二聚体和抗 CD8 mAb 治疗小鼠异位心脏同种异体移植受者。用p40同型二聚体治疗同种异体移植受体对产生IFN-γ的细胞的体内致敏没有影响，并且相对于未修饰的受体导致同种异体移植排斥加速。然而，p40 同二聚体显着延长了 CD8+ T 细胞耗尽的小鼠同种异体移植物的存活时间。因此，p40 同二聚体在体外刺激 CD8+ Th1 发育，但在体外和体内抑制 CD4+ T 细胞功能。
The role of IL-12 role in regulating Th1/Th2 balance is attributed in part to the ability of this cytokine to induce IFNgamma production by NK and Th1 cells, which in turn promotes Th1 and inhibits Th2 development. In the present study, the requirement for IL-12 in the development of alloantigen-reactive Th1 was assessed by adding neutralizing anti-IL-12 Abs or the IL-12 receptor antagonist p40 homodimer to primary MLC. The resulting cell populations were assessed for Th1 development by measuring IFN-gamma production upon restimulation with alloantigens. While the addition of anti-IL-12 Abs to primary MLC did not influence subsequent cytokine production, addition of p40 homodimer markedly enhanced, rather than decreased, Th1 development. To determine which T cell population produced enhanced levels of IFN-gamma in response to p40 homodimer, CD4+ or CD8+ T cells were depleted from the MLC. While p40 homodimer was inhibitory to selected CD4+ Th1 development, it enhanced IFN-gamma production by CD8+ T cells. To test the in vivo relevance of these findings, mouse heterotopic cardiac allograft recipients were treated with either p40 homodimer, anti-CD8 mAb, or with both p40 homodimer and anti-CD8 mAb. Treatment of allograft recipients with p40 homodimer had no effect on the in vivo sensitization of IFN-gamma-producing cells and resulted in accelerated allograft rejection relative to unmodified recipients. However, p40 homodimer markedly prolonged allograft survival in mice depleted of CD8+ T cells. Hence, p40 homodimer stimulates CD8+ Th1 development in vitro but inhibits CD4+ T cell function both in vitro and in vivo.