Induced and natural regulatory T cells in the development of inflammatory bowel disease

Abstract

The mucosal immune system mediates contact between the host and the trillions of microbes that symbiotically colonize the gastrointestinal tract. Failure to tolerate the antigens within this "extended self" can result in inflammatory bowel disease (IBD). Within the adaptive immune system, the most significant cells modulating this interaction are Foxp3 regulatory T (Treg) cells. Treg cells can be divided into 2 primary subsets: "natural" Treg cells and "adaptive" or "induced" Treg. Recent research suggests that these subsets serve to play both independent and synergistic roles in mucosal tolerance. Studies from both mouse models and human patients suggest that defects in Treg cells can play distinct causative roles in IBD. Numerous genetic, microbial, nutritional, and environmental factors that associate with IBD may also affect Treg cells. In this review, we summarize the development and function of Treg cells and how their regulatory mechanisms may fail, leading to a loss of mucosal tolerance. We discuss both animal models and studies of patients with IBD suggesting Treg cell involvement in IBD and consider how Treg cells may be used in future therapies.

Figures

Figure 1

Model of Treg cell development. The nTreg (green) and Tconv (grey) cell populations develop as separate lineages in the thymus, based in part on differences in the threshold for affinity-based selection. The result is a peripheral population of nTreg and Tconv cells with distinct TCR (orange) repertoires. In the gut and at other environmental interfaces, TGF-β1 induces Tconv cells to become iTreg cells (red) or Th17 cells (purple). The peripheral Treg cell pool is therefore comprised of both iTreg and nTreg cells that share suppressive mechanisms such as IL-10 production. Increased levels of IL-6 in the local environment promote production of Th17 cells while blocking iTreg cell formation. In general, iTreg cells are unstable and may lose Foxp3 expression (ex-iTreg cells), although certain factors may increase iTreg stability. The ex-iTreg cells (pink) are available to become Th1 (blue) or Th17 cells, or to reacquire Foxp3 expression and cycle back into the iTreg pool. Importantly, nTreg and iTreg cells act synergistically and are non-redundant, a feature based largely on their different TCR repertoires.