Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA.
J Immunol. 2010 Jun 15;184(12):6649-57. doi: 10.4049/jimmunol.0903729. Epub 2010 May 14.
T cells present in lymphopenic environments undergo spontaneous (homeostatic) proliferation resulting in expansion of the memory T cell pool. Homeostatically generated memory T cells protect the host against infection but can cause autoimmunity and allograft rejection. Therefore, understanding the mechanisms that regulate homeostatic T cell proliferation is germane to clinical settings in which lymphodepletion is used. In this study, we asked whether NK cells, which regulate immune responses in lymphocyte-replete hosts, also regulate homeostatic T cell proliferation under lymphopenic conditions. We found that T cells transferred into genetically lymphocyte-deficient RAG-/- mice proliferate faster and generate more CD8+ memory T cells if NK cells were absent. CD8+ T cells that underwent homeostatic proliferation in the presence of NK cells generated mostly effector memory (CD44highCD62Llow) lymphocytes, whereas those that divided in the absence of NK cells were skewed toward central memory (CD44highCD62Lhigh). The latter originated predominantly from proliferation of the "natural" central memory CD8+ T cell pool. Regulation of homeostatic proliferation by NK cells occurred independent of perforin but was reversed by excess IL-15. Importantly, NK depletion enhanced CD8+ T cell recovery in T cell-depleted wild-type mice and accelerated rejection of skin allografts, indicating that regulation of homeostatic proliferation by NK cells is not restricted to genetically lymphocyte-deficient animals. These results demonstrate that NK cells downregulate homeostatic CD8+ T cell proliferation in lymphopenic environments by competing for IL-15. Concomitant NK and T cell depletion may be undesirable in transplant recipients because of enhanced expansion of memory CD8+ T cells that increase the risk of rejection.
在淋巴缺失环境中，T 细胞会发生自发（稳态）增殖，导致记忆 T 细胞池的扩增。稳态产生的记忆 T 细胞可以保护宿主免受感染，但也可能导致自身免疫和同种异体移植物排斥。因此，了解调节稳态 T 细胞增殖的机制与淋巴缺失用于临床环境有关。在这项研究中，我们想知道 NK 细胞是否会在淋巴缺失条件下调节稳态 T 细胞增殖，这些细胞在淋巴细胞丰富的宿主中调节免疫反应。我们发现，如果没有 NK 细胞，转移到遗传上淋巴细胞缺乏的 RAG-/- 小鼠中的 T 细胞会更快地增殖，并产生更多的 CD8+记忆 T 细胞。在 NK 细胞存在的情况下进行稳态增殖的 CD8+T 细胞主要产生效应记忆（CD44highCD62Llow）淋巴细胞，而在没有 NK 细胞的情况下分裂的细胞则偏向于中央记忆（CD44highCD62Lhigh）。后者主要来源于“天然”中央记忆 CD8+T 细胞池的增殖。NK 细胞对稳态增殖的调节独立于穿孔素，但可以被过量的 IL-15 逆转。重要的是，NK 细胞耗竭增强了 T 细胞耗竭的野生型小鼠中 CD8+T 细胞的恢复，并加速了皮肤同种异体移植物的排斥，表明 NK 细胞对稳态增殖的调节不仅限于遗传上淋巴细胞缺乏的动物。这些结果表明，NK 细胞通过竞争 IL-15 来下调淋巴缺失环境中的稳态 CD8+T 细胞增殖。由于记忆 CD8+T 细胞的扩增增加了排斥的风险，同时耗竭 NK 和 T 细胞可能不是移植受者所期望的。
