Cellular and molecular requirements for rejection of B16 melanoma in the setting of regulatory T cell depletion and homeostatic proliferation.
Cellular and molecular requirements for rejection of B16 melanoma in the setting of regulatory T cell depletion and homeostatic proliferation.
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DOI：
10.4049/jimmunol.1100845
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发表时间：
2012-03-15
期刊：
影响因子：
--
通讯作者：
Gajewski TF
中科院分区：
文献类型：
--
作者：
Kline J;Zhang L;Battaglia L;Cohen KS;Gajewski TF
我们最近已经证明，过继转移的调节性T细胞（Treg）耗尽的多克隆T细胞到淋巴细胞减少的小鼠导致排斥B16黑色素瘤，这产生了一个机会，研究肿瘤排斥反应时，它有效地发生主机的要求。CD 8 + T细胞引发和肿瘤排斥需要肿瘤抗原交叉呈递，如Kb−/−骨髓嵌合或B71/2−/−小鼠中的肿瘤生长所证明。另外，最佳肿瘤控制需要CD 4 + T细胞，认为不是通过经典的CD 4“帮助”，因为在不存在CD 4 + T细胞的情况下，致敏的CD 8 + T细胞的频率是相似的，并且肿瘤排斥不依赖于CD 40/CD 40 L相互作用或CD 4 + T细胞的IL-2产生。相反，CD 4 + T细胞似乎在肿瘤排斥的效应期起作用，并在体外对B16衍生的抗原作出反应。在效应期，需要由转移的T细胞而不是宿主细胞产生IFN-γ。IFN-γ作用于宿主或肿瘤细胞，并与肿瘤血管减少有关。最后，在转移TNF-α、穿孔素或FasL缺陷的T细胞后发生肿瘤排斥。然而，穿孔素/FasL双敲除T细胞未能排斥，认为B16黑色素瘤细胞的杀伤可能通过细胞毒性颗粒或Fas途径发生。总的来说，这些结果支持宿主肿瘤抗原交叉呈递引发过继转移的T细胞的模型，所述过继转移的T细胞在稳态增殖和Treg耗竭的情况下保持功能性，并且通过IFN-γ促进肿瘤排斥和通过细胞毒性颗粒和/或FasL促进裂解。
We have recently demonstrated that adoptive transfer of regulatory T cell (Treg) - depleted polyclonal T cells into lymphopenic mice leads to rejection of B16 melanoma, which generated an opportunity to study host requirements for tumor rejection when it effectively occurred. CD8+ T cell priming and tumor rejection required tumor antigen cross-presentation, as evidenced by tumor outgrowth in Kb−/− bone marrow chimeric or B71/2−/− mice. CD4+ T cells were additionally required for optimal tumor control, thought not through classical CD4 “help”, as the frequency of primed CD8+ T cells was similar in the absence of CD4+ T cells, and tumor rejection did not depend upon CD40/CD40L interactions or on IL-2 production by CD4+ T cells. Rather, CD4+ T cells appeared to act at the effector phase of tumor rejection and responded to B16-derived antigens in vitro. At the effector phase, IFN-γ production by transferred T cells, but not host cells, was necessary. IFN-γ acted either on host or tumor cells, and was associated with reduced tumor vascularity. Finally, tumor rejection occurred following transfer of TNF-α, perforin or FasL-deficient T cells. However, perforin/FasL double knockout T cells failed to reject, arguing that that the killing of B16 melanoma cells could occur either via the cytotoxic granule or Fas pathways. Collectively, these results support a model in which host tumor antigen cross-presentation primes adoptively-transferred T cells, which remain functional in the setting of homeostatic proliferation and Treg depletion, and which promote tumor rejection via IFN-γ and lysis via cytotoxic granules and/or FasL.
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