Functional Pairing Of GPR15-C100RF99 Initiates The First Colonic Treg Cell Homing Response In Amniotes

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,in a healthy or diseased state.Treg homing to the small intestine mediated by the CCR9–CCL25 pair has been studied extensively and is evolutionarily conserved in all vertebrates.However,the origin of Treg homing to the colon(large intestines)remains mysterious because the colon emerged in tetrapods after vertebrates evolved.Here,we found that the C10ORF99 peptide(a cognate ligand of GPR15 that controls Treg homing to the colon)originated from duplication of the flanking CDHR1 gene and functionally paired with GPR15 in amniotes.Evolutionary analysis and experimental data indicated that the GPR15–C10ORF99 pair is functionally conserved for colonic Treg homing in amniotes and that their expression patterns are positively correlated with an herbivore diet in the colon.Our findings also highlight that GPCR receptor–ligand pairing leads to physiological adaptation during vertebrate evolution.With the first herbivorous diet in early amniotes,a new biological process(herbivorous diet–short-chain fatty acid–C10ORF99/GPR15–Treg homing–colon immune homeostasis)emerged,and we propose an evolutionary model whereby GPR15–C10ORF99 functional pairing initiated the first colonic Treg homing reaction in amniotes.