Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
EMBO Rep. 2022 Feb 3;23(3):e53246. doi: 10.15252/embr.202153246. Epub 2021 Dec 23.
Regulatory T lymphocyte (Treg) homing reactions mediated by G protein-coupled receptor (GPCR)-ligand interactions play a central role in maintaining intestinal immune homeostasis by restraining inappropriate immune responses in the gastrointestinal tract. However, the origin of Treg homing to the colon remains mysterious. Here, we report that the C10ORF99 peptide (also known as CPR15L and AP57), a cognate ligand of GPR15 that controls Treg homing to the colon, originates from a duplication of the flanking CDHR1 gene and is functionally paired with GPR15 in amniotes. Evolutionary analysis and experimental data indicate that the GPR15-C10ORF99 pair is functionally conserved to mediate colonic Treg homing in amniotes and their expression patterns are positively correlated with herbivore diet in the colon. With the first herbivorous diet in early amniotes, a new biological process (herbivorous diet short-chain fatty acid-C10ORF99/GPR15-induced Treg homing colon immune homeostasis) emerged, and we propose an evolutionary model whereby GPR15-C10ORF99 functional pairing has initiated the first colonic Treg homing reaction in amniotes. Our findings also highlight that GPCR-ligand pairing leads to physiological adaptation during vertebrate evolution.
调节性 T 淋巴细胞 (Treg) 通过 G 蛋白偶联受体 (GPCR)-配体相互作用介导的归巢反应在维持肠道免疫稳态中起核心作用，通过限制胃肠道中不适当的免疫反应。然而，Treg 归巢到结肠的起源仍然是个谜。在这里，我们报告 C10ORF99 肽（也称为 CPR15L 和 AP57），一种控制 Treg 归巢到结肠的 GPR15 的同源配体，来源于侧翼 CDHR1 基因的重复，并且在羊膜动物中与 GPR15 具有功能配对。进化分析和实验数据表明，GPR15-C10ORF99 对在羊膜动物中介导结肠 Treg 归巢具有功能保守性，其表达模式与结肠中食草动物饮食呈正相关。随着早期羊膜动物中首次出现食草性饮食，一种新的生物学过程（食草性饮食短链脂肪酸-C10ORF99/GPR15 诱导的 Treg 归巢结肠免疫稳态）出现了，我们提出了一个进化模型，其中 GPR15-C10ORF99 功能配对在羊膜动物中引发了第一次结肠 Treg 归巢反应。我们的研究结果还强调，GPCR-配体配对导致了脊椎动物进化过程中的生理适应。
