Background: Regulatory T cells (Tregs) have potential anti-inflammatory effects and are likely to be important in the pathogenesis of chronic inflammatory bowel disease (IBD). However, the induction and expansion of Tregs at sites of mucosal inflammation is not yet fully understood and may involve antigen presentation by local dendritic cells and/or intestinal epithelial cells (IECs).
Methods: To determine the unique ways of the gut to induce or expand Tregs we made use of a transgenic mouse model that is based on the specific expression of a model auto-antigen (influenza HA) in the intestinal epithelium (VILLIN-HA). Gut-associated dendritic cells (DCs) and intestinal epithelial cells (IECs) isolated from these mice were phenotypically and functionally characterized for the potential to interact with HA-specific Tregs in vitro and in vivo.
Results: Intestinal self-antigen expression leads to peripheral expansion of antigen-specific CD4+Foxp3+ Tregs. Although gut-associated DCs can induce antigen-specific CD4+Foxp3+ T cell proliferation, in vivo depletion of DCs did not preclude proliferation of these cells. Interestingly, antigen presentation by primary IECs is sufficient to efficiently expand antigen specific CD4+Foxp3+ Tregs. This is dependent on MHC class II but in contrast to DCs unlikely to require TGF-beta and retinoic acid.
Conclusion: This study provides experimental evidence for a new concept in mucosal immunity: in contrast to current thinking, expansion of Tregs can be achieved independent of local DCs through antigen-specific IEC - T cell interactions.