T cell tolerance and immunity to commensal bacteria

Abstract

The commensal bacteria normally resident in the gastrointestinal tract represent an enormous pool of foreign antigen within the body. Although mechanical barriers limit entry of bacteria into the host, recent data suggest that T cells routinely interact with commensal bacteria using both antigen-specific and non-specific receptors. Depending on the bacterial species, either regulatory or effector T cell responses can be generated. For example, segmented filamentous bacteria (SFB) favor effector Th17 responses whereas Bacteroides fragilis and certain Clostridium species favor Foxp3+ regulatory T (Treg) cell responses. Thus, in contrast with the notion that only tolerogenic responses are required to self, gut homeostasis may require both tolerance and immunity to various constituents of the commensal microbiota.

Figure 1. A hypothetical model of T cell-mediated gut homeostasis

(Left) During homeostasis, commensal bacteria primarily induce iTreg cell differentiation (green cell), although some bacteria (e.g. SFB) may elicit effector T (Teff) cell responses (orange). iTreg cells would then inhibit effector cell responses to commensal bacteria, as well as inhibit effector T cell differentiation. This may limit immunopathology and permit healing of transient breaks in the mucosal barrier. It is unclear whether iTreg cells block effector responses to bacteria which the Treg cells do not recognize. We hypothesize that the effector cells generated during normal conditions may serve to keep certain commensal bacterial species from causing pathology. (Middle) During infection, the influx of pathogenic bacteria induces differentiation of antigen-specific effector T cells (yellow). Pre-existing Treg cells specific to commensal bacteria may suppress effector responses to commensal bacteria (orange cell) to prevent additional immunopathology. Whether commensal bacteria-specific iTreg cells also suppress the pathogen-specific response is unclear. The inflammatory response to pathogen may also inhibit iTreg cell differentiation (not depicted). (Right) During resolution, iTreg cells limit excessive pathology to the commensal bacteria that pass through the healing mucosal barrier.