Foxp3+ regulatory T (T reg) cells play a key role in controlling immune pathological re actions. Many develop their regulatory activity in the thymus, but there is also evidence for development of Foxp3+ T reg cells from naive precursors in the periphery. Recent studies have shown that transforming growth factor (TGF)-β can promote T reg cell development in culture, but little is known about the cellular and molecular mechanisms that mediate this pathway under more physiological conditions. Here, we show that after antigen activation in the intestine, naive T cells acquire expression of Foxp3. Moreover, we identify a population of CD103+ mesenteric lymph node dendritic cells (DCs) that induce the devel opment of Foxp3+ T reg cells. Importantly, promotion of T reg cell responses by CD103+ DCs is dependent on TGF-β and the dietary metabolite, retinoic acid (RA). These results newly identify RA as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.

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A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism

The abundance of innate and adaptive immune cells that reside together with trillions of beneficial commensal microorganisms in the mammalian gastrointestinal tract requires barrier and regulatory mechanisms that conserve host-microbial interactions and tissue homeostasis. This homeostasis depends on the diverse functions of intestinal epithelial cells (IECs), which include the physical segregation of commensal bacteria and the integration of microbial signals. Hence, IECs are crucial mediators of intestinal homeostasis that enable the establishment of an immunological environment permissive to colonization by commensal bacteria. In this Review, we provide a comprehensive overview of how IECs maintain host-commensal microbial relationships and immune cell homeostasis in the intestine.

Intestinal epithelial cells: regulators of barrier function and immune homeostasis

To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3+ T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4+ T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ–derived DCs. This enhanced conversion by LpDCs was dependent on TGF-β and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.

/pdf/small-intestine-lamina-propria-dendritic-cells-promote-de-jachbvfx4i.pdf

Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid

A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.

CCR7 and its ligands: balancing immunity and tolerance

The intestinal immune system must elicit robust immunity against harmful pathogens but must also restrain immune responses directed against commensal microbes and dietary antigens. The mechanisms that maintain this dichotomy are poorly understood. Here we describe a population of CD11b+F4/80+CD11c- macrophages in the lamina propria that expressed several anti-inflammatory molecules, including interleukin 10 (IL-10), but little or no proinflammatory cytokines, even after stimulation with Toll-like receptor ligands. These macrophages induced, by a mechanism dependent on IL-10, retinoic acid and exogenous transforming growth factor-beta, the differentiation of Foxp3+ regulatory T cells. In contrast, lamina propria CD11b+ dendritic cells elicited IL-17 production. This IL-17 production was suppressed by lamina propria macrophages, indicating that a dynamic interaction between these subsets may influence the balance between immune activation and tolerance.

Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses.

Gut-associated lymphoid tissue (GALT) dendritic cells (DCs) display a unique ability to generate CCR9 + α 4 β 7 + gut-tropic CD8 + effector T cells. We demonstrate efficient induction of CCR9 and α 4 β 7 on CD8 + T cells in mesenteric lymph nodes (MLNs) after oral but not intraperitoneal (i.p.) antigen administration indicating differential targeting of DCs via the oral route. In vitro, lamina propria (LP)–derived DCs were more potent than MLN or Peyer's patch DCs in their ability to generate CCR9 + α 4 β 7 + CD8 + T cells. The integrin α chain CD103 ( α E) was expressed on almost all LP DCs, a subset of MLN DCs, but on few splenic DCs. CD103 + MLN DCs were reduced in number in CCR7 − / − mice and, although CD8 + T cells proliferated in the MLNs of CCR7 − / − mice after i.p. but not oral antigen administration, they failed to express CCR9 and had reduced levels of α 4 β 7. Strikingly, although CD103 + and CD103 − MLN DCs were equally potent at inducing CD8 + T cell proliferation and IFN- γ production, only CD103 + DCs were capable of generating gut-tropic CD8 + effector T cells in vitro. Collectively, these results demonstrate a unique function for LP-derived CD103 + MLN DCs in the generation of gut-tropic effector T cells.

https://rupress.org/jem/article-pdf/202/8/1063/1128631/jem20281063.pdf

Caroline Palmqvist

Papers

Functional specialization of gut CD103^+ dendritic cells in the regulation of tissue-selective T cell homing