Department of Immunology, Center for Integrated Immunology and Vaccine Research, University of Connecticut Health Center, Farmington, CT 06030, USA.
J Immunol. 2010 Dec 1;185(11):6857-65. doi: 10.4049/jimmunol.1001601. Epub 2010 Nov 1.
IL-15 operates via a unique mechanism termed transpresentation. In this system, IL-15 produced by one cell type is bound to IL-15Rα expressed by the same cell and is presented to apposing cells expressing the IL-15Rβ/γC complex. We have shown that administering soluble IL-15Rα complexed with IL-15 can greatly enhance IL-15 activity. We now show that the naive CD8 T cell response to exogenous IL-15/IL-15Rα complex is MHC class I dependent. In the absence of β2 microglobulin, naive CD8 T cells scarcely proliferated in response to IL-15/IL-15Rα complex, whereas memory cells proliferated, although to a lesser extent, compared with levels in control mice. The loss of β2m or FcRn slightly reduced the extended half-life of IL-15/IL-15Rα complex, whereas FcRn deficiency only partially reduced the naive CD8 T cell proliferative response to IL-15/IL-15Rα complex. In addition, we demonstrated a link between TCR avidity and the ability of a T cell to respond to IL-15/IL-15Rα complex. Thus, T cells expressing low-avidity TCR responded poorly to IL-15/IL-15Rα complex, which correlated with a poor homeostatic proliferative response to lymphopenia. The inclusion of cognate peptide along with complex resulted in enhanced proliferation, even when TCR avidity was low. IL-15/IL-15Rα complex treatment, along with peptide immunization, also enhanced activation and the migratory ability of responding T cells. These data suggest that IL-15/IL-15Rα complex has selective effects on Ag-activated CD8 T cells. Our findings have important implications for directing IL-15/IL-15Rα complex-based therapy to specific Ag targets and illustrate the possible adjuvant uses of IL-15/IL-15Rα complex.
白细胞介素-15（IL-15）通过一种称为转呈的独特机制发挥作用。在这个系统中，一种细胞类型产生的 IL-15 与同一细胞表达的 IL-15Rα 结合，并呈递给表达 IL-15Rβ/γC 复合物的相邻细胞。我们已经表明，施用与 IL-15 结合的可溶性 IL-15Rα 复合物可以大大增强 IL-15 的活性。我们现在表明，外源性 IL-15/IL-15Rα 复合物对幼稚 CD8 T 细胞的反应依赖于 MHC Ⅰ类。在缺乏β2 微球蛋白的情况下，幼稚 CD8 T 细胞几乎不会对 IL-15/IL-15Rα 复合物增殖，而记忆细胞虽然增殖程度较小，但与对照小鼠相比有所增加。β2m 或 FcRn 的缺失略微降低了 IL-15/IL-15Rα 复合物的延长半衰期，而 FcRn 缺陷仅部分降低了幼稚 CD8 T 细胞对 IL-15/IL-15Rα 复合物的增殖反应。此外，我们证明了 TCR 亲合力与 T 细胞对 IL-15/IL-15Rα 复合物反应能力之间存在联系。因此，表达低亲合力 TCR 的 T 细胞对 IL-15/IL-15Rα 复合物反应不佳，这与对淋巴细胞减少症的稳态增殖反应不佳相关。与复合物一起包含同源肽导致增殖增强，即使 TCR 亲合力较低也是如此。IL-15/IL-15Rα 复合物治疗加上肽免疫还增强了应答 T 细胞的激活和迁移能力。这些数据表明，IL-15/IL-15Rα 复合物对 Ag 激活的 CD8 T 细胞具有选择性作用。我们的发现对指导基于 IL-15/IL-15Rα 复合物的治疗针对特定 Ag 靶标具有重要意义，并说明了 IL-15/IL-15Rα 复合物的可能佐剂用途。
