Glycoantigens Induce Human Peripheral Tr1 Cell Differentiation with Gut-homing Specialization

The carbohydrate antigen (glycoantigen) PSA from an intestinal commensal bacteria is able to down-regulate inflammatory bowel disease in model mice, suggesting that stimulation with PSA results in regulatory T cell (Treg) generation. However, mechanisms of how peripheral human T cells respond and home in response to commensal antigens are still not understood. Here, we demonstrate that a single exposure to PSA induces differentiation of human peripheral CD4(+) T cells into type-Tr1 Tregs. This is in contrast to mouse models where PSA induced the production of Foxp3(+) iTregs. The human PSA-induced Tr1 cells are profoundly anergic and exhibit nonspecific bystander suppression mediated by IL-10 secretion. Most surprisingly, glycoantigen exposure provoked expression of gut homing receptors on their surface. These findings reveal a mechanism for immune homeostasis in the gut whereby exposure to commensal glycoantigens provides the requisite information to responding T cells for proper tissue localization (gut) and function (anti-inflammatory/regulatory).