In addition to pro-inflammatory immune responses mediated Th1 and Th17 cells, there are anti-inflammatory immune responses occurring in the gut mucosa. First, to prevent the exposure of immune cells to antigens in the gut lumen, mucus covers the epithelial layers. In addition, anti-microbial peptides secreted by Paneth cells and immunoglobulin A (IgA) secreted by B cells can block the invasion of gut microbes into the tissues. As an active suppression of pro-inflammatory immune responses, regulatory T cells exist in abundance in gut mucosa and promote anti-inflammatory immune responses. Both pro- and anti-inflammatory immune responses are affected by dietary and microbial by-products (such as Ahr ligands, polysaccharide A, and short-chain fatty acids).
Inflammation is a critical element of how the immune system functions to eliminate foreign pathogens, injured cells, and tumors. However, excess inflammation can be harmful to the host and to counteract this process, the immune system has also evolved to modulate anti-inflammatory responses. This equilibrium between pro- and anti-inflammatory immune responses, termed “immune homeostasis”, is critical for the health of the host. While disruption of immune homeostasis can occur systemically, it can also be localized to a specific tissue as seen in inflammatory disorders such as psoriasis, inflammatory bowel diseases, and tumors, thus underscoring the importance of immune homeostasis at tissue level in maintaining health. However, at present, we have an extremely limited understanding of how immune homeostasis is maintained locally in non-lymphoid tissues. Furthermore, local immune balance can be affected by other factors perturbing tissue environment, such as diet (in the intestine), commensal microbiota or infectious pathogens (in the intestine, skin, and other mucosal surfaces), adding another element of complexity.
As a postdoctoral fellow, I started the quest to understand the mechanisms at play to preserve immune homeostasis in the intestine. My work led to the discovery of a novel T cell homing receptor to the large intestine, GPR15, which is induced by the gut microbiota, and unraveled that this orphan GPCR contributes to maintenance of an optimal balance of pro- and anti-inflammatory responses in the large intestine through the preferential recruitment of regulatory T cells (Tregs) (Kim SV et al., Science, 2013).
In my laboratory, I plan on continuing studies to dissect the mechanisms underlying immune homeostasis in non-lymphoid tissues (peripheral tissues) such as the intestine, by focusing not only on GPR15 but also beyond, by setting up novel approaches, with the hope that such findings can be used to develop therapeutic methods for restoring the immune balance that is lost in inflammatory or infectious diseases and cancer. More specifically, I will first focus on the mechanisms of T cell homing to the intestine, how immune tolerance to gut microbiota is maintained and microbial antigens recognized by T cells.