Data_Sheet_6_Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response.PDF

Related interleukin-2, -15, and -15-like (IL-2, -15, and -15L) are ancient cytokines, with all three genes surviving in extant fish and some mammals. The present study is the first to identify IL-15L functions, namely in rainbow trout. In isolated trout splenocytes, and in vivo, purified recombinant IL-15L+IL-15Rα molecules induced expression of IL-4 and IL-13 homologs, which are markers of type 2 immunity. In contrast, trout IL-15 stimulated type 1 immunity markers, thus IL-15 and IL-15L can have opposing functions. Trout IL-15L was more dependent on “in trans” presentation by the receptor chain IL-15Rα than IL-15, and stimulated CD4−CD8−(IgM−) lymphocytes from thymus and spleen. We propose an important role for IL-15L early in the type 2 immunity cytokine cascade. Trout IL-2 and IL-15 exhibited features reminiscent of their mechanistic and functional dichotomy observed in mammals; for example, IL-15 but not IL-2 required a receptor alpha chain (only IL-15Rα in the case of fish) for its stability, and only IL-15 was efficient in stimulating lymphocytes from mucosal tissues. Data suggest that IL-15L and IL-15 may be particularly effective in stimulating innate lymphocyte type 2 cells (ILC2) and natural killer (NK) cells, respectively, but further identification of the cell types is needed. An interesting finding different from in mammals was the efficient stimulation of CD4+CD8+ thymocytes by IL-2. In short, this study presents fundamental information on the evolution of the IL-2/15/15L cytokine family.

白细胞介素-2、白细胞介素-15及白细胞介素-15样蛋白（IL-2、IL-15、IL-15L）属于古老的细胞因子家族，三类基因在现存鱼类与部分哺乳动物中均得以保留。本研究首次明确了IL-15L的生物学功能，实验以虹鳟为研究对象。在分离的虹鳟脾淋巴细胞及活体状态下，纯化的重组IL-15L与IL-15Rα复合物可诱导IL-4与IL-13同源基因的表达，这两类分子是2型免疫的标志性标志物。与之相反，虹鳟IL-15可诱导1型免疫标志物的表达，提示IL-15与IL-15L的功能存在拮抗效应。相较于IL-15，虹鳟IL-15L更依赖受体链IL-15Rα的反式呈递（in trans），且可刺激胸腺与脾脏来源的CD4⁻CD8⁻(IgM⁻)淋巴细胞。本研究提出，IL-15L在2型免疫细胞因子级联反应的早期阶段发挥关键调控作用。虹鳟IL-2与IL-15的特征与哺乳动物中报道的二者功能及机制的二分特性高度相似：例如，IL-15的稳定性依赖受体α链（鱼类中仅存在IL-15Rα），而IL-2无此依赖；且仅IL-15可有效激活黏膜组织来源的淋巴细胞。数据显示，IL-15L与IL-15或许可分别高效激活2型固有淋巴细胞（ILC2）与自然杀伤（NK）细胞，但仍需进一步明确其作用的细胞亚群。与哺乳动物研究结果不同的是，本研究发现IL-2可有效激活CD4⁺CD8⁺胸腺细胞。综上，本研究为IL-2/15/15L细胞因子家族的演化历程提供了基础性研究数据。