Institute of Biochemistry, Molecular Cell Biology, University Clinic Hamburg-Eppendorf, 0251 Hamburg, Germany.
PM Research Center, 20 Kaggeholm, Ekerö, 178 54 Stockholm, Sweden.
Genes (Basel). 2021 May 26;12(6):813. doi: 10.3390/genes12060813.
Understanding the evolution of interleukins and interleukin receptors is essential to control the function of CD4+ T cells in various pathologies. Numerous aspects of CD4+ T cells' presence are controlled by interleukins including differentiation, proliferation, and plasticity. CD4+ T cells have emerged during the divergence of jawed vertebrates. However, little is known about the evolution of interleukins and their origin. We traced the evolution of interleukins and their receptors from Placozoa to primates. We performed phylogenetic analysis, ancestral reconstruction, HH search, and positive selection analysis. Our results indicated that various interleukins' emergence predated CD4+ T cells divergence. IL14 was the most ancient interleukin with homologs in fungi. Invertebrates also expressed various interleukins such as IL41 and IL16. Several interleukin receptors also appeared before CD4+ T cells divergence. Interestingly IL17RA and IL17RD, which are known to play a fundamental role in Th17 CD4+ T cells first appeared in mollusks. Furthermore, our investigations showed that there is not any single gene family that could be the parent group of interleukins. We postulate that several groups have diverged from older existing cytokines such as IL4 from TGFβ, IL10 from IFN, and IL28 from BCAM. Interleukin receptors were less divergent than interleukins. We found that IL1R, IL7R might have diverged from a common invertebrate protein that contained TIR domains, conversely, IL2R, IL4R and IL6R might have emerged from a common invertebrate ancestor that possessed a fibronectin domain. IL8R seems to be a GPCR that belongs to the rhodopsin-like family and it has diverged from the Somatostatin group. Interestingly, several interleukins that are known to perform a critical function for CD4+ T cells such as IL6, IL17, and IL1B have gained new functions and evolved under positive selection. Overall evolution of interleukin receptors was not under significant positive selection. Interestingly, eight interleukin families appeared in lampreys, however, only two of them (IL17B, IL17E) evolved under positive selection. This observation indicates that although lampreys have a unique adaptive immune system that lacks CD4+ T cells, they could be utilizing interleukins in homologous mode to that of the vertebrates' immune system. Overall our study highlights the evolutionary heterogeneity within the interleukins and their receptor superfamilies and thus does not support the theory that interleukins evolved solely in jawed vertebrates to support T cell function. Conversely, some of the members are likely to play conserved functions in the innate immune system.
了解白细胞介素及其受体的进化对于控制各种病理条件下 CD4+T 细胞的功能至关重要。白细胞介素控制着 CD4+T 细胞的存在的诸多方面，包括分化、增殖和可塑性。CD4+T 细胞在有颌脊椎动物的分化过程中出现。然而，关于白细胞介素及其起源的进化知之甚少。我们从扁盘动物到灵长类动物追踪了白细胞介素及其受体的进化。我们进行了系统发育分析、祖先重建、HH 搜索和正选择分析。我们的结果表明，各种白细胞介素的出现早于 CD4+T 细胞的分化。IL14 是最古老的白细胞介素，在真菌中有同源物。无脊椎动物也表达了各种白细胞介素，如 IL41 和 IL16。几个白细胞介素受体也出现在 CD4+T 细胞分化之前。有趣的是，已知在 Th17 CD4+T 细胞中发挥重要作用的 IL17RA 和 IL17RD 首先出现在软体动物中。此外，我们的研究表明，没有任何一个基因家族可以作为白细胞介素的母群。我们推测，有几个基因簇是从现有的细胞因子如 IL4 从 TGFβ、IL10 从 IFN 和 IL28 从 BCAM 分化而来的。白细胞介素受体的进化程度不如白细胞介素。我们发现，IL1R、IL7R 可能来自于一种含有 TIR 结构域的无脊椎动物蛋白，相反，IL2R、IL4R 和 IL6R 可能来自于一种具有纤维连接蛋白结构域的无脊椎动物祖先。IL8R 似乎是一种属于视紫红质样家族的 GPCR，它是从生长抑素组中分化出来的。有趣的是，一些已知对 CD4+T 细胞具有关键功能的白细胞介素，如 IL6、IL17 和 IL1B，获得了新的功能，并在正选择下进化。白细胞介素受体的总体进化并没有受到显著的正选择。有趣的是，八个白细胞介素家族出现在七鳃鳗中，然而，只有两个家族（IL17B、IL17E）在正选择下进化。这一观察结果表明，尽管七鳃鳗具有独特的适应性免疫系统，缺乏 CD4+T 细胞，但它们可以利用白细胞介素以类似于脊椎动物免疫系统的同源方式发挥作用。总体而言，我们的研究强调了白细胞介素及其受体超家族内部的进化异质性，因此不支持白细胞介素仅在有颌脊椎动物中进化以支持 T 细胞功能的理论。相反，其中一些成员可能在先天免疫系统中发挥保守功能。
