Regulation of IL-22 biology is directed by many routes. Regulation of IL-22 biology is directed by many routes. IL-22 is mainly produced by CD4 T cells and ILC3s (top left) and regulated by the transcription factors STAT3, AHR, and MAPKs. Many environmental factors control this production, including commensal bacteria (top right). Secreted IL-22 stimulates GI tract epithelial cells (bottom left), leading to STAT3 activation and production of mucins and antimicrobial proteins as well as increasing cellular proliferation and fucosylation. These factors in turn regulate the commensal bacteria. DCs (bottom right) are a source of IL-22BP, an IL-22R homolog that binds to IL-22 with higher affinity than the IL-22R and inhibits IL-22–mediated signaling in target cells. Although many regulatory factors are known for each of these routes, many gaps in our knowledge exist, as represented by question marks (?). This figure was drawn using pictures from Servier Medical Art under a Creative Commons Attribution 3.0 Unported License. Lauren A. Zenewicz ImmunoHorizons 2018;2:198-207 Copyright © 2018 The Authors