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Differential T cell homing to colon vs. small intestine is imprinted by local CD11c⁺ APCs that determine homing receptors.

ABSTRACT: Mechanisms that imprint T cell homing to the small intestine have been well studied; however, those for homing to the colon are poorly understood. Recently, we found that these are distinct subcompartments of the gut mucosal immune system, which implies differential homing. Here, we show that colonic CD11c⁺ APCs imprint CD8⁺ T cell preferential homing to the colon, in contrast to those from the small intestine that imprint CD8⁺ T cell homing to the small intestine, and that the differences are related to the variable ability of APCs to induce ?4?7-integrin and CCR9 expression on T cells. Colon APCs also expressed lower levels of retinoic acid-producing enzymes that are known to control the mucosal homing of T cells. These findings are the first to our knowledge to directly demonstrate that colon APCs imprint T cells to selectively home to the large bowel, which is critical for the design of successful T cell-based therapies and vaccines, such as colon cancer immunotherapy and HIV vaccines.

SUBMITTER: Dzutsev A

PROVIDER: S-EPMC5669635 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Differential T cell homing to colon vs. small intestine is imprinted by local CD11c+ APCs that determine homing receptors.

Dzutsev Amiran A Hogg Alison A Sui Yongjun Y Solaymani-Mohammadi Shahram S Yu Huifeng H Frey Blake B Wang Yichuan Y Berzofsky Jay A JA

Journal of leukocyte biology 20170926 6

Mechanisms that imprint T cell homing to the small intestine have been well studied; however, those for homing to the colon are poorly understood. Recently, we found that these are distinct subcompartments of the gut mucosal immune system, which implies differential homing. Here, we show that colonic CD11c+ APCs imprint CD8+ T cell preferential homing to the colon, in contrast to those from the small intestine that imprint CD8+ T cell homing to the small intestin ...[more]

PMID: 28951425

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Project description:The gut-brain axis, a reciprocal interaction between the central nervous system (CNS) and peripheral intestinal functions, is conceptually feasible from recent clinical and experimental evidence showing mutual interactions between the CNS and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel diseases (IBDs) and CNS disorders. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including induction and maintenance of peripheral regulatory T cells (pTregs) and what environmental cues prompt the host to protect host from development of IBDs. Here, we report a novel liver-brain-gut neural arc that ensures proper differentiation and maintenance of peripheral regulatory T cells (pTregs) in the gut. The hepatic vagal sensory afferents were responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius (NTS) of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level significantly impaired colonic pTregs, which was attributed to impairment of aldehyde dehydrogenase (ALDH) expression and retinoic acid (RA) synthesis by intestinal antigen-presenting cells (APCs). Muscarinic Ach receptor (mAChR) activation directly induced ALDH gene expression both in human and mouse colonic APCs, whereas genetic ablation of mAChRs abolished APC excitement in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in colitis models reduced the colonic pTreg pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc tunes the number of pTregs and maintains the gut homeostasis. Intervening in this autonomic feedback feed-forward system could help develop new therapeutic strategies to treat or prevent immunological disorders of the gut.

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Differential T cell homing to colon vs. small intestine is imprinted by local CD11c⁺ APCs that determine homing receptors.

Publications

Differential T cell homing to colon vs. small intestine is imprinted by local CD11c<sup>+</sup> APCs that determine homing receptors.

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