Key Points Gal-3−/− CD8+ T cells exhibit increased apoptosis following agonist aOX40 therapy. Gal-3−/− CD8+ T cells are skewed towards effector/effector memory subsets. Decreased survival was cell intrinsic and associated with higher Erdr1 expression. CD8+ T cells are critical mediators of adaptive immunity, and enhancing their function can promote robust responses against invading pathogens and neoplastic cells. In addition to TCR stimulation, the provision of costimulation through ligation of TNFR family members, such as OX40 (CD134), provides essential signals driving T cell differentiation, survival, and memory in part through enhanced IL-2/IL-2R signaling. Interestingly, TCR stimulation in the presence of IL-2 upregulates intracellular expression of the β-galactoside binding protein, Galectin-3 (Gal-3). Gal-3 has been shown to regulate Th1/Th2 polarization of CD4+ T cells; however, the extent to which Gal-3 regulates the OX40/IL-2 signaling axis and CD8+ T cell proliferation, effector function, and/or survival is unknown. In this study, we demonstrate that murine Gal-3–deficient CD8+ T cells exhibited no defects in early (36 h) activation or proliferation following TCR stimulation. In contrast, Gal-3−/− CD8+ T cells exhibited decreased survival and a reduced capacity to develop into memory cells following stimulation with cognate Ag plus agonist anti-OX40 mAb or IL-2 in vivo. Decreased survival of Gal-3−/− T cells was associated with increased apoptosis and occurred in a cell-intrinsic manner. Together, these data implicate intracellular Gal-3 as a critical mediator of OX40-mediated CD8+ T cell survival and memory formation following Ag exposure.

中文翻译：

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细胞内 Galectin-3 对于 OX40 介导的记忆 CD8+ T 细胞发育至关重要

关键点 Gal-3-/- CD8+ T 细胞在激动剂 aOX40 治疗后表现出增加的细胞凋亡。Gal-3-/- CD8+ T 细胞偏向于效应器/效应器记忆亚群。存活率降低是细胞内在的，并且与更高的 Erdr1 表达相关。CD8+ T 细胞是适应性免疫的关键介质，增强它们的功能可以促进对入侵病原体和肿瘤细胞的强烈反应。除了 TCR 刺激外，通过连接 TNFR 家族成员（如 OX40 (CD134)）提供的共刺激部分通过增强的 IL-2/IL-2R 信号提供驱动 T 细胞分化、存活和记忆的基本信号。有趣的是，在 IL-2 存在下的 TCR 刺激上调了 β-半乳糖苷结合蛋白 Galectin-3 (Gal-3) 的细胞内表达。Gal-3 已被证明可以调节 CD4+ T 细胞的 Th1/Th2 极化；然而，Gal-3 调节 OX40/IL-2 信号轴和 CD8+ T 细胞增殖、效应子功能和/或存活的程度尚不清楚。在这项研究中，我们证明小鼠 Gal-3 缺陷型 CD8+ T 细胞在 TCR 刺激后的早期（36 小时）激活或增殖中没有表现出缺陷。相比之下，Gal-3-/- CD8+ T 细胞在体内用同源 Ag 加激动剂抗 OX40 mAb 或 IL-2 刺激后表现出存活率降低和发育成记忆细胞的能力降低。Gal-3-/- T 细胞存活率降低与细胞凋亡增加有关，并以细胞内在方式发生。总之，这些数据表明细胞内 Gal-3 是 OX40 介导的 CD8+ T 细胞存活和银暴露后记忆形成的关键介质。