Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Department of Surgery, Guthrie Robert Packer Hospital, Sayre, PA 18840.
J Immunol. 2020 Jun 15;204(12):3227-3235. doi: 10.4049/jimmunol.1901276. Epub 2020 May 11.
Lymphopenia-induced homeostatic proliferation (LIP) is a critical mechanism for restoring T cell immunity upon lymphodepleting insults or infections. LIP is primarily driven by homeostatic cytokines, such as IL-7 and IL-15, but not all T cells respond with the same efficiency to homeostatic proliferative cues. Although CD8 T cells vigorously proliferate under lymphopenic conditions, naive CD4 T cells are substantially impaired in their response to homeostatic cytokines, and they fail to fully expand. In this study, we show that the availability of IL-2Rβ (CD122), which is a receptor subunit shared by IL-2 and IL-15, affects both the cytokine responsiveness and the LIP of naive CD4 T cells in the mouse. The enumeration of surface IL-2Rβ molecules on murine naive CD4 and naive CD8 T cells revealed a 5-fold difference in IL-2Rβ abundance. Notably, it was the limited availability of IL-2Rβ that impaired CD4 T cell responsiveness to IL-15 and suppressed their LIP. As such, forced IL-2Rβ expression on CD4 T cells by transgenesis bestowed IL-15 responsiveness onto naive CD4 T cells, which thus acquired the ability to undergo robust LIP. Collectively, these results identify IL-2Rβ availability as a new regulatory mechanism to control cytokine responsiveness and the homeostatic proliferation of murine CD4 T cells.
淋巴细胞减少诱导的稳态增殖（Lymphopenia-induced homeostatic proliferation，LIP）是在淋巴耗竭性损伤或感染后恢复 T 细胞免疫的关键机制。LIP 主要由稳态细胞因子（如 IL-7 和 IL-15）驱动，但并非所有 T 细胞对稳态增殖信号的反应效率相同。虽然 CD8 T 细胞在淋巴减少的情况下会剧烈增殖，但幼稚 CD4 T 细胞对稳态细胞因子的反应受到严重损害，无法完全扩增。在这项研究中，我们表明，IL-2Rβ（CD122）的可用性，即 IL-2 和 IL-15 共享的受体亚基，会影响小鼠幼稚 CD4 T 细胞的细胞因子反应性和 LIP。对小鼠幼稚 CD4 和幼稚 CD8 T 细胞表面 IL-2Rβ 分子的计数显示，IL-2Rβ 的丰度存在 5 倍的差异。值得注意的是，正是 IL-2Rβ 的有限可用性损害了 CD4 T 细胞对 IL-15 的反应性，并抑制了它们的 LIP。因此，通过转基因使 CD4 T 细胞强制表达 IL-2Rβ，赋予了幼稚 CD4 T 细胞对 IL-15 的反应性，从而使其获得了进行强烈 LIP 的能力。总之，这些结果确定了 IL-2Rβ 的可用性是控制细胞因子反应性和小鼠 CD4 T 细胞稳态增殖的新调节机制。
