CD4+Foxp3+ regulatory T cell expansion induced by antigen-driven interaction with intestinal epithelial cells independent of local dendritic cells

Background: Regulatory T cells (T-regs) 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 T-regs at sites of mucosal inflammation are not yet fully understood and may involve antigen presentation by local dendritic cells (DCs) and/or intestinal epithelial cells (IECs). Methods: To determine the unique ways in which the gut induces or expands T-regs,T- a transgenic mouse model that is based on the specific expression of a model autoantigen (influenza haemagglutinin (HA)) in the intestinal epithelium (VILLIN-HA) was used. Gut-associated DCs and IECs isolated from these mice were phenotypically and functionally characterised for the potential to interact with HA-specific T-regs in vitro and in vivo. Results: Intestinal self-antigen expression leads to peripheral expansion of antigen-specific CD4(+)Foxp3(+) T-regs. 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 expand antigen-specific CD4(+)Foxp3(+) T-regs efficiently. This is dependent on major histocompatibility complex class II, but, in contrast to DCs, is unlikely to require transforming growth factor beta and retinoic acid. Conclusion: This study provides experimental evidence for a new concept in mucosal immunity: in contrast to current thinking, expansion of T-regs can be achieved independently of local DCs through antigen-specific IEC-T cell interactions.