Aruga A, Aruga E, Tanigawa K, Bishop D K, Sondak V K, Chang A E
Department of Surgery, University of Michigan, Ann Arbor 48109, USA.
J Immunol. 1997 Jul 15;159(2):664-73.
We have previously reported that CD8+ tumor-draining lymph node (TDLN) cells activated with anti-CD3 and IL-2-mediated tumor regression in adoptive immunotherapy. In this study, we examined the TCR Vbeta repertoire usage of TDLN cells with respect to cytokine release profiles and therapeutic efficacy in vivo. The majority of the whole population of TDLN cells after activation with anti-CD3 were composed of Vbeta3+, -5+, -7+, -8+, and -11+ cells. Enrichment of Vbeta subsets of TDLN cells by in vitro activation with anti-Vbeta mAb revealed Vbeta8+ cells released high amounts of IFN-gamma and granulocyte/macrophage-CSF (GM-CSF) with minimal amounts of IL-10 in response to tumor and mediated tumor regression in vivo. In contrast, enriched populations of Vbeta5+, Vbeta7+, and Vbeta11+ cells released low amounts of IFN-gamma and GM-CSF with high levels of IL-10 and had no in vivo antitumor reactivity. In vitro depletion of specific Vbeta subsets from the whole TDLN pool confirmed that the profile of cytokines released correlated with in vivo antitumor function. Therapeutic efficacy mediated by TDLN cells required the release of IFN-gamma and GM-CSF since in vivo neutralization of both cytokines inhibited tumor regression. The administration of anti-IL-10 mAb abrogated the suppressed antitumor response manifested by adoptively transferred TDLN cells, which elaborated increased levels of IL-10. Our study documents that type 1 cytokine release (i.e., IFN-gamma and GM-CSF) promotes in vivo tumor Ag recognition, in contrast to type 2 release (i.e., IL-10), which suppresses this interaction, and discriminates the functional activity of Vbeta subpopulations of effector cells.
我们之前报道过，在过继性免疫治疗中，用抗CD3和白细胞介素-2激活的CD8⁺肿瘤引流淋巴结（TDLN）细胞介导肿瘤消退。在本研究中，我们检测了TDLN细胞的TCR Vβ谱型使用情况与体内细胞因子释放谱及治疗效果的关系。用抗CD3激活后，TDLN细胞总体中的大多数由Vβ3⁺、-5⁺、-7⁺、-8⁺和-11⁺细胞组成。用抗Vβ单克隆抗体体外激活使TDLN细胞的Vβ亚群富集，结果显示Vβ8⁺细胞在接触肿瘤时释放大量干扰素-γ和粒细胞/巨噬细胞集落刺激因子（GM-CSF），而白细胞介素-10释放量极少，并在体内介导肿瘤消退。相比之下，Vβ5⁺、Vβ7⁺和Vβ11⁺细胞的富集群体释放少量的干扰素-γ和GM-CSF，白细胞介素-10水平较高，且无体内抗肿瘤反应性。从整个TDLN库中体外去除特定的Vβ亚群证实，释放的细胞因子谱与体内抗肿瘤功能相关。TDLN细胞介导的治疗效果需要干扰素-γ和GM-CSF的释放，因为体内中和这两种细胞因子均会抑制肿瘤消退。给予抗白细胞介素-10单克隆抗体可消除过继转移的TDLN细胞所表现出的被抑制的抗肿瘤反应，这些细胞产生的白细胞介素-10水平有所升高。我们的研究证明，与抑制这种相互作用的2型细胞因子释放（即白细胞介素-10）相反，1型细胞因子释放（即干扰素-γ和GM-CSF）促进体内肿瘤抗原识别，并区分效应细胞Vβ亚群的功能活性。
