Contextual functions of antigen-presenting cells in the gastrointestinal tract

Abstract

The immune system of the gastrointestinal tract must be tightly regulated to limit pathologic responses toward innocuous antigens while simultaneously allowing for rapid development of effector responses against invading pathogens. Highly specialized antigen-presenting cell (APC) subsets present in the gut play a dominant role in balancing these seemingly disparate functions. In this review, we discuss new findings associated with the function of gut APCs and particularly the contextual role of these cells in both establishing tolerance to orally acquired antigens in the steady state and regulating acute inflammation during infection.

Keywords: Treg; antigen-presenting cell; commensal; dendritic cell; immune regulation; macrophage; monocyte; mucosal; pathogen.

Fig. 1. Induction and maintenance of the steady state intestinal T-cell compartment

In the steady state, highly specialized antigen-presenting cells (APCs) enriched in the gut-associated lymphoid tissue (GALT) are crucial to establish the tolerogenic Forkhead box protein 3 (Foxp3)⁺ regulatory T-cell (Treg) network as well as effector T cells (Teff) that help maintain the mucosal barrier. CD103⁺ dendritic cells (DCs) carry dietary derived and commensal antigens to the mesenteric lymph node (mesLN), where their unique capacity to produce both active TGF-β and the vitamin A metabolite retinoic acid (RA) favors induction of Foxp3⁺ Treg from naive T cells. Additionally, RA supports the acquisition of gut-homing markers by these cells that potentiates their capacity to traffic back to the small intestine and colon lamina propria. Upon arrival in the gut, newly converted Foxp3⁺ Treg are maintained/expanded by IL-10-producing CX3CR1^hi macrophages. These induced Foxp3⁺ Tregs along with their thymus-derived counterparts act to limit local immune activation stimulated by food and commensal antigens. CD103 DCs in the mesLN also secrete IL-6, which synergizes with TGF-β signaling to induce Th17 effector cells.. Lamina propria-resident Th17 cells modulate epithelial cell function and anti-microbial peptide secretion. Although poorly understood, a similar network of regulatory and effector T cells may be re-established in the context of chronic pathogen infection to limit unwanted ongoing immune responses towards the long-lived invader.

Fig. 2. Regulation of effector T-cell responses and recruited inflammatory cells

As well as favoring tolerance to dietary and commensal antigens, gut antigen-presenting cells (APCs) also regulate development of effector T-cell (Teff) responses towards commensals and pathogens and limit uncontrolled inflammatory cell activation during infection. Gut APCs are exquisitely sensitive to conserved commensal and pathogen-associated molecular patterns (PAMPs), due to their expression of a broad array of pathogen recognition receptors (PRRs). Notably, in response to microbial ligands, previously tolerogenic APCs become potent inducers of Th17 and Th1 responses as a result of their capacity to make IL-6 and IL-12, respectively. In this setting, the capacity of CD103⁺ DCs to produce RA supports T-cell activation and homing back to the intestine. Additionally, at the peak of the inflammatory response towards a pathogen, recruited Ly6C^hi effector monocytes can acquire regulatory features to prevent lethal neutrophil-mediated immunopathology. This is mediated by their ability to make prostaglandin E₂ (PGE₂), a potent suppressor of neutrophil activation, in response to commensal ligands.