T-cell selection and intestinal homeostasis

Abstract

Although intestinal bacteria live deep within the body, they are topographically on the exterior surface and thus outside the host. According to the classic notion that the immune system targets non-self rather than self, these intestinal bacteria should be considered foreign and therefore attacked and eliminated. While this appears to be true for some commensal bacterial species, recent data suggest that the immune system actively becomes tolerant to many bacterial organisms. The induction or activation of regulatory T (Treg) cells that inhibit, rather than promote, inflammatory responses to commensal bacteria appears to be a central component of mucosal tolerance. Loss of this mechanism can lead to inappropriate immune reactivity toward commensal organisms, perhaps contributing to mucosal inflammation characteristic of disorders such as inflammatory bowel disease.

Keywords: T cell; T-cell receptors; inflammatory bowel disease; mucosa.

Fig. 1. Different microenvironments in the gut allow for antagonistic T-cell differentiation despite a tolerogenic macroenvironment

The macroenvironment of the intestines is enriched with SCFAs which have been reported to induce tolerogenic factors including TGFβ. Antigens may be delivered to CD103⁺ DCs in the lamina propria via GAPs and muc2, or they may reside within the epithelium and acquire bacteria via intraepithelial dendrites. Muc2 and SCFAs may stimulate these DCs to secrete TGFβ, retinoic acid, and IDO, creating a microenvironment that directs pTreg cell differentiation. CX₃CR1⁺CD103⁻DCs may acquire antigens via transepithelial dendrites during inflammation, and secrete cytokines enriched with pro-inflammatory factors such as IL-6. Thus, the microenvironment in which a naive T-cell encounters their antigen may direct whether they adopt a tolerogenic or effector fate. Note that although this figure illustrates naive T-cell encounter with APCs in the intestinal lamina propria, this phenomenon may first occur in the mesenteric lymph node and involve migratory DCs (–93, 138).

Fig. 2. The myriad of immune responses to commensal bacteria

Recent studies have demonstrated a clear relationship between specific commensal species, APCs, and T-cell fates. Many studies report the total numbers of Treg and effector cells that arise from interaction with commensal bacteria, but the mechanisms behind these interactions remain unclear. For example, which commensal bacterial species elicit Treg, Th1, and Th17 cells? How is the antigen taken up, and by which APCs? Do they induce subsets of Treg cells expressing effector transcription factors like RORγt? Interestingly, like Treg cells, Th17 cells have recently been suggested to be comprised of subsets with different pathogenicity and developmental requirements (139, 140). Could these subsets of Th17 cells be related to Treg cells by transcription factors or TCR specificities? Thus, this diagram illustrates the complex relationships that exist between commensal bacteria and the T cell immune system as well as the myriad of factors that should be investigated in future experiments.

Fig. 3. Effector and Treg cell responses to pathogenic and commensal bacteria

(A). Effector response to gut bacteria. Under homeostatic conditions, gut resident effector T cells (red) mediate sub-clinical immune response toward commensal bacteria (blue), limiting lamina propria invasion. This subclinical response may also provide protection against pathogenic bacteria (red). During infection, invasive pathogens promote a robust effector T-cell response, leading to their eventual clearance. Simultaneous presentation of commensal antigens during this inflammation can lead to the expansion of commensal-specific effector T cells. Sustained inflammation may lead to feed-forward loop (right) where commensal-T cells alone can maintain inflammation and promote immune response toward additional commensal bacteria and, eventually, overt colitis. (B). Regulatory response to gut bacteria. Under homeostatic conditions, commensal bacteria (orange) drive peripheral conversion of naïve T cells to a regulatory phenotype via the action of tolerogenic dendritic cells (DCs) (green). Pathogens (red) may be able to subvert this process to prevent their elimination by effector cells, potentially leading to the sustained inflammation described in (A). Pathogens that gain access to tolerogenic DCs may lead to generation of Treg rather than effector T cells. Pathogens that share epitopes (yellow star) with commensal bacteria may be protected by commensal-specific regulatory responses.