Microbe-dendritic cell dialog controls regulatory T-cell fate

Abstract

Each microenvironment is controlled by a specific set of regulatory elements that have to be finely and constantly tuned to maintain local homeostasis. These environments could be site specific, such as the gut environment, or induced by chronic exposure to microbes. Various populations of dendritic cells are central to the orchestration of this control. In this review, we discuss some new findings associating dendritic cells from defined compartments with the induction and control of regulatory T cells in the context of exposure to both commensal and pathogenic microbes.

Fig.1. Control of regulatory T cells in the GI tract

(A) Steady state/chronic infection. At steady state, several subsets of small intestine DCs are exposed to luminal antigens derived from gut flora or food. Of particular importance, CD103⁺ DCs metabolize vitamin A to retinoic acid (RA), which is able to favor conversion of Foxp3⁺ Tregs by directly acting on naive T cells and limiting effector cytokine release by activated T cells. Expansion of neoconverted Foxp3⁺ Tregs, along with other induced Foxp3⁺ Treg (iTregs) and natural Foxp3⁺ Tregs that make up the peripheral Treg pool, is further supported by the availability of IL-2 or other common γ chain cytokines (e.g. IL-7, IL-15). Subsequently, this compartment acts as one layer of regulation within the gut environment to limit local immune activation stimulated by luminal antigens. A similar scenario may occur in the context of chronic infection in which conversion needs to be maintained in the face of an ongoing immune response. As a consequence chronic pathogens may have co-evolved to release factors that enhance the conversion process, such as TGF-β. (B) Acute infection. In the presence of an acute infection, such as infection with Toxoplasma gondii, peripheral Foxp3⁺ Treg conversion is inhibited. This inhibition is in part mediated by the influx of inflammatory DC subsets into tissue sites. By releasing pro-inflammatory cytokines, including IL-12 or IL-27, these DCs support the expansion of IFN-γ secreting Th1 cells. IFN-γ directly inhibits the Foxp3⁺ Treg conversion process. In addition limitation of IL-2 in Th1 polarized environments hinders the development of this compartment. Moreover, IL-12 from inflammatory DC subsets can drive expression of T-bet within previously Foxp3⁺ Treg allowing them to adapt to the inflammatory within the tissue. All these mechanisms act together to favor a controlled effector response towards the invading pathogen. However, in highly inflammatory circumstances expression of T-bet may eventually drive IFN-γ production in regulatory T cells. In this situation the breakdown of the conversion process along with expression of effector cytokines by Foxp3⁺ Tregs may potentially result in severe pathogenesis.

Fig.1. Control of regulatory T cells in the GI tract

(A) Steady state/chronic infection. At steady state, several subsets of small intestine DCs are exposed to luminal antigens derived from gut flora or food. Of particular importance, CD103⁺ DCs metabolize vitamin A to retinoic acid (RA), which is able to favor conversion of Foxp3⁺ Tregs by directly acting on naive T cells and limiting effector cytokine release by activated T cells. Expansion of neoconverted Foxp3⁺ Tregs, along with other induced Foxp3⁺ Treg (iTregs) and natural Foxp3⁺ Tregs that make up the peripheral Treg pool, is further supported by the availability of IL-2 or other common γ chain cytokines (e.g. IL-7, IL-15). Subsequently, this compartment acts as one layer of regulation within the gut environment to limit local immune activation stimulated by luminal antigens. A similar scenario may occur in the context of chronic infection in which conversion needs to be maintained in the face of an ongoing immune response. As a consequence chronic pathogens may have co-evolved to release factors that enhance the conversion process, such as TGF-β. (B) Acute infection. In the presence of an acute infection, such as infection with Toxoplasma gondii, peripheral Foxp3⁺ Treg conversion is inhibited. This inhibition is in part mediated by the influx of inflammatory DC subsets into tissue sites. By releasing pro-inflammatory cytokines, including IL-12 or IL-27, these DCs support the expansion of IFN-γ secreting Th1 cells. IFN-γ directly inhibits the Foxp3⁺ Treg conversion process. In addition limitation of IL-2 in Th1 polarized environments hinders the development of this compartment. Moreover, IL-12 from inflammatory DC subsets can drive expression of T-bet within previously Foxp3⁺ Treg allowing them to adapt to the inflammatory within the tissue. All these mechanisms act together to favor a controlled effector response towards the invading pathogen. However, in highly inflammatory circumstances expression of T-bet may eventually drive IFN-γ production in regulatory T cells. In this situation the breakdown of the conversion process along with expression of effector cytokines by Foxp3⁺ Tregs may potentially result in severe pathogenesis.