Lineage-specific ablation of retinoic acid synthesis impacts on the development of gut-tropic regulatory T cells and oral tolerance

Oral tolerance is a multifaceted process that leads to systemic unresponsiveness to orally administrated antigens. Successful establishment of oral tolerance relies on induction of antigen-specific gut-tropic regulatory T cells (Tregs). Retinoic acid (RA), the active metabolite of vitamin A, is critical for the induction of gut-homing receptor on T cells and differentiation of Foxp3+ Tregs. Current paradigm, developed from in vitro experimentation, suggests that CD103+ RA-producing dendritic cells (DCs) are critical for mediating mucosal tolerance. However, in vivo evidence supporting this statement is lacking, due to the challenge of lineage-specific ablation of RA. We developed a novel mouse model to ablate RA synthesis in defined cell lineages and evaluate the requirement of RA for the migration, retention and stability of gut-tropic Tregs in different intestinal compartments. We found that RA regulates the development of gut-tropic Tregs cells in a step-wise process by lineage-specific up-regulation of gut-homing receptors. Furthermore, evaluation of the establishment of oral tolerance in an oral Listeria infection model revealed that suppression of immunity against Listeria was less efficient when RA synthesis is ablated. Collectively, this is the first study that elucidates the role of RA for oral tolerance in vivo, and offers novel insight into how RA fine-tunes the balance between gut immunity and tolerance.