Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
J Immunol. 2013 May 1;190(9):4627-39. doi: 10.4049/jimmunol.1201854. Epub 2013 Mar 27.
The TNFR family member 4-1BB plays a key role in the survival of activated and memory CD8 T cells. However, the mechanisms that regulate 4-1BB re-expression on memory CD8 T cells after Ag clearance are unknown. In unimmunized mice, ∼10% of CD8 CD44(hi) memory T cells in the bone marrow (BM) and liver express 4-1BB, with minimal 4-1BB expression in spleen and lymph node. IL-2, IL-15, and IL-7 are collectively dispensable for 4-1BB expression on the memory CD8 T cells. Rather, T cell-intrinsic glucocorticoid-induced TNFR-related protein (GITR) contributes to 4-1BB expression on CD8 T cells upon their entry into the BM or liver. Consistent with its role in regulation of 4-1BB, GITR is required on memory CD8 T cells for their persistence in vivo. These findings reveal site-specific effects of the BM and liver microenvironment on CD8 memory T cells. Previous work has demonstrated that 4-1BB agonists given to unimmunized mice induce splenomegaly, hepatitis, and other immune system anomalies. Moreover, severe liver pathology has been observed in a subset of anti-4-1BB-treated melanoma patients. Remarkably, the absence of GITR in mice almost completely abrogates cellular expansions, splenomegaly, and liver inflammation associated with anti-4-1BB agonist treatment of unimmunized mice. In contrast, lack of CD8 T cells selectively improves liver pathology, but not splenomegaly in the mice. Thus, the regulation of 4-1BB expression by GITR on CD8 T cells, as well as on other cells, contributes to the pathological effects of anti-4-1BB in unimmunized mice.
肿瘤坏死因子受体家族成员 4-1BB 在激活和记忆 CD8 T 细胞的存活中发挥关键作用。然而，调节抗原清除后记忆 CD8 T 细胞上 4-1BB 再表达的机制尚不清楚。在未免疫的小鼠中，骨髓（BM）和肝脏中约 10%的 CD8 CD44(hi)记忆 T 细胞表达 4-1BB，而脾脏和淋巴结中 4-1BB 的表达很少。IL-2、IL-15 和 IL-7 共同对记忆 CD8 T 细胞上的 4-1BB 表达是可有可无的。相反，T 细胞内在糖皮质激素诱导的 TNF 受体相关蛋白（GITR）有助于 CD8 T 细胞进入 BM 或肝脏时 4-1BB 的表达。与其在调节 4-1BB 中的作用一致，GITR 在体内记忆 CD8 T 细胞的持久性中是必需的。这些发现揭示了 BM 和肝脏微环境对 CD8 记忆 T 细胞的特定作用。先前的工作表明，给予未免疫的小鼠 4-1BB 激动剂会导致脾肿大、肝炎和其他免疫系统异常。此外，在一部分接受抗 4-1BB 治疗的黑色素瘤患者中观察到严重的肝病理学。值得注意的是，GITR 在小鼠中的缺失几乎完全消除了与未免疫的小鼠用抗 4-1BB 激动剂治疗相关的细胞扩增、脾肿大和肝脏炎症。相比之下，缺乏 CD8 T 细胞选择性地改善了小鼠的肝脏病理学，但不能改善脾肿大。因此，GITR 在 CD8 T 细胞以及其他细胞上对 4-1BB 表达的调节有助于解释抗 4-1BB 在未免疫小鼠中的病理作用。
