Regulatory T cells and immune tolerance in the intestine

Abstract

A fundamental role of the mammalian immune system is to eradicate pathogens while minimizing immunopathology. Instigating and maintaining immunological tolerance within the intestine represents a unique challenge to the mucosal immune system. Regulatory T cells are critical for continued immune tolerance in the intestine through active control of innate and adaptive immune responses. Dynamic adaptation of regulatory T-cell populations to the intestinal tissue microenvironment is key in this process. Here, we discuss specialization of regulatory T-cell responses in the intestine, and how a breakdown in these processes can lead to chronic intestinal inflammation.

Figure 1.

Properties of Foxp3⁺ Treg from thymic and extrathymic origins.

Figure 2.

Foxp3⁺ Treg specialization on microenvironment adaptation maintains mucosal immune tolerance. (A) Gata3-dependent mechanisms promote Foxp3 expression and regulation of mucosal Th2 responses. Whether these mechanisms are distinct is not known. (B) CNS1 deficiency and loss of Foxp3⁺ iTreg-mediated regulation of mucosal Th2 responses may occur through cell-extrinsic (absolute requirement for Foxp3⁺ iTreg in control of Th2 responses) or cell-intrinsic (naïve T-cell precursors to Foxp3⁺ iTreg deviate to Th2 phenotype in absence of CNS1) mechanisms.

Figure 3.

Commensal microbiota and dietary metabolites influence intestinal T-cell adaptation to direct mucosal and peripheral immune responses. The intestinal mucosa is constantly exposed to a diverse array of foreign antigens, including dietary antigens, metabolites, and components of the commensal microbiota. The presence of distinct microbial species promotes specialized host immune responses through differentiation of appropriate effector and regulatory T-cell populations. Segmented filamentous bacteria promote effector T-cell accumulation, particularly of Th17 cells, within the intestine. Accumulation of Foxp3⁺ regulatory T-cell populations and induction of IL-10 production arise in response to colonization of germ-free mice with a restricted flora (Clostridiales IV and XIVa, or Altered Schaedler Flora), or conventionally housed mice with Helicobacter hepaticus. In both cases, the mechanism of induction and antigen-specificity of the response require further investigation. Antigen-presenting cell production of soluble mediators heavily influences the balance between effector and regulatory T-cell responses. Production of STAT3 activating cytokines (IL-6, IL-23, IL-21) favors effector T-cell differentiation, whereas retinoic acid (RA) and TGF-β1 production modulate the balance between effector and regulatory responses, depending on the inflammatory microenvironment and associated cytokine production.