Inflammation must be effective, while limiting excessive tissue damage. To walk this line, immune functions are grossly compartmentalized by innate cells that act locally and adaptive cells that function systemically. But what about the myriad tissue-resident immune cells that are critical to this balancing act and lie on a spectrum of innate and adaptive immunity? We propose that mammalian perivascular adventitial 'cuffs' are conserved sites in multiple organs, enriched for these tissue-resident lymphocytes and dendritic cells, as well as lymphatics, nerves, and subsets of specialized stromal cells. Here, we argue that these boundary sites integrate diverse tissue signals to regulate the movement of immune cells and interstitial fluid, facilitate immune crosstalk, and ultimately act to coordinate regional tissue immunity.