Abstract

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, 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 β 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.