Antigen-specific regulatory T-cell responses to intestinal microbiota

Abstract

The mammalian gastrointestinal tract can harbor both beneficial commensal bacteria important for host health, but also pathogenic bacteria capable of intestinal damage. It is therefore important that the host immune system mount the appropriate immune response to these divergent groups of bacteria-promoting tolerance in response to commensal bacteria and sterilizing immunity in response to pathogenic bacteria. Failure to induce tolerance to commensal bacteria may underlie immune-mediated diseases such as human inflammatory bowel disease. At homeostasis, regulatory T (Treg) cells are a key component of the tolerogenic response by adaptive immunity. This review examines the mechanisms by which intestinal bacteria influence colonic T-cells and B-cell immunoglobulin A (IgA) induction, with an emphasis on Treg cells and the role of antigen-specificity in these processes. In addition to discussing key primary literature, this review highlights current controversies and important future directions.

Figure 1. Antigen Specific and Non-Specific Mechanisms of Bacteria-Induced Treg Cell Generation and Function

Clostridium spp. establish an environment favorable for pTreg cell generation via the induction of TGFβ secretion by intestinal epithelial cells (IECs) (purple arrow), IDO in IECs and APCs (red arrows), and the production of SCFAs from dietary components (blue). Bacteroides spp. such as B. fragilis have been described to increase Treg cell function through PSA activation of TLR2 ligation on T cells and DCs (grey arrows). PSA, as well as SCFAs (blue arrow), induce IL-10 secretion from LP Treg cells. SCFAs also act directly on T cells to induce Treg differentiation/expansion. Dietary vitamin A from the intestinal lumen (orange arrows) can enhance pTreg cell differentiation through its metabolite retinoic acid, which can affect pTreg cell selection by inducing transcription factor binding to a Foxp3 enhancer element in CNS1^-, or via blockade of effector cytokine production by effector T cells. Bacterial antigens (green arrow), may gain access to immune cells by a variety of mechanisms that are currently unclear, including via goblet-associated passages, transcytosis through IECs, extension of APC processes into the intestinal lumen, or direct invasion of whole bacteria^, . Naïve T cells have been reported to encounter commensal antigens in the mesenteric lymph node and undergo pTreg cell selection. The Peyer's patches and isolated lymphoid follicles may also be important sites of pTreg cell selection, but this requires further study.

Figure 2. Alternative Regulation of Intestinal Bacterial Antigen Presentation and T Cell Fate in Lymphoreplete vs. Lymphopenic Mice

In lymphoreplete mice, commensal spp. induce naïve colonic TCR transgenic CT2/CT6 cells into Treg cells. Based on in vitro and in vivo studies, it is predicted that select Bacteroides and Clostridium spp. induce antigen-specific Treg cells in lymphoreplete mice. However, naive CT2/CT6 T cells develop into effector T cells in Rag1^−/− lymphopenic mice. In contrast to the behavior of of CT2/CT6, CBir1 antigen, a component of flagella present in many gut bacteria species including those in Clostridium subphylum XIVa, does not activate T cells or induce differentiation of Treg cells in lymphoreplete mice. However, these antigens are presented in lymphopenic mice leading to T cell activation and IgA production. Mucosal injury or infection will also lead to antigen presentation to CBir1 reactive T cells. In these environments, CBir1 reactive T cells become effector, and not Treg, cells.