The Heteromeric Dopamine Receptor D2:D3 Controls the Gut Recruitment and Suppressive Activity of Regulatory T-Cells

Since colonic dopamine levels undergo a sharp reduction in inflammatory bowel disease (IBD) and animal models, we study how dopaminergic signalling affects regulatory T cells (Treg), which are critical limiting gut inflammation. Previously, we showed that the stimulation of the high-affinity dopamine receptor Drd3 impairs the suppressive Treg ac-tivity and limits their colonic tropism upon gut inflammation. Here we study the role of the low-affinity dopamine receptor Drd2 in Treg, finding that stimulation of Drd2 favours the suppressive Treg activity and promotes their colonic tropism. Transcriptomic analysis of intestinal mucosa from IBD patients revealed an association with increased DRD3 and reduced DRD2 expression. Biochemical approaches revealed that Drd2 and Drd3 form a heteromeric receptor. Competition assays using α-helix peptides analogue to the trans-membrane (TM) segments from Drd2 and Drd3 showed that TM5 from Drd2 (TM5Drd2) and TM2Drd3 and TM6Drd3 disrupt the assembly of this heteromer. The Drd2:Drd3 het-eromer was expressed on colonic Treg, and its expression was increased upon inflamma-tion. The heteromer disassembly dampened the suppressive Treg activity and impaired their colonic tropism upon inflammation. Our findings indicate that the Drd2:Drd3 het-eromer constitutes a dopamine sensor that plays a critical role on the suppressive Treg ac-tivity and colonic tropism.