Immunometabolism Sentinels: Gut Surface T-Cells Regulate GLP-1 Availability

Intestinal intraepithelial T-cells (IELs) are resident T-lymphocytes located in the epithelium of the small intestine. These adaptive immune cells promote immune tolerance and influence gut barrier function by rapidly responding to microbial and dietary antigens (1). Although IELs protect against enteric pathogens, this lymphocyte population contributes to more than immunity. Exciting data published by He et al. (2) in Nature demonstrate that IELs participate in the endocrine control of whole body metabolism by regulating bioavailability of the hormone glucagon-like peptide 1 (GLP-1).

He et al. (2) found that lymphocytes such as αβ and γδ T-cells, B cells, and myeloid cells in the mouse small intestine had high expression of the transmembrane receptor integrin β7. This receptor is responsible for homing leukocytes to the gut. After testing several mixed cell chimeric mouse models, the authors demonstrated that mice with itgb7 deficiency (i.e., β7^−/−) in intraepithelial αβ and γδ T-cells had improved blood glucose control, thereby linking these intestinal lymphocytes to energy metabolism.

The authors showed that IELs regulate blood glucose, lipids, and energy balance in lean and obese mice. Lean β7^−/− mice (with lower IELs) had higher energy expenditure associated with augmented brown fat activity. Additionally, β7^−/− mice had lower blood triglycerides and improved blood glucose control associated with increased insulin production. These effects extend to models of metabolic disease, given that β7^−/− mice fed a diet high in fat, sugar, and sodium were protected against obesity, hypertension, and dysglycemia. Antibody or hematopoietic depletion of β7 also protected against atherosclerosis in Ldlr^−/− mice. Altogether, these results demonstrate that targeting this integrin receptor in the gut attenuates key features of the metabolic syndrome. The authors then determined the endocrine factor that could propagate intestinal sensing to glycemic, lipid, and cardiovascular effects.

Deletion of integrin β7 in mice increased circulating GLP-1, which is an incretin hormone produced by intestinal L-cells upon luminal nutrient sensing. GLP-1 slows down gut motility, promotes satiety, inhibits glucagon secretion, and augments insulin secretion (3). The GLP-1 receptor (GLP-1R) is expressed in intestinal αβ and γδ T lymphocytes. β7^−/− mice had lower GLP-1R expression in IELs and increased intestinal L-cell density. Furthermore, elegant evidence supported the notion that IELs could act as a local gut-resident sink that could capture locally produced GLP-1 and limit bioavailable GLP-1. In particular, extensive in vitro coculture and ex vivo experiments using purified small intestinal IELs demonstrated that GLP-1R resident on IELs can bind to GLP-1, decreasing the concentration of GLP-1 that would otherwise be available to leave the local gut environment and interact with GLP-1R on other cells. This finding is relevant because IELs entrapped GLP-1 but appeared not to engage systemic GLP-1R metabolic responses. The findings suggest that GLP-1R–expressing IELs regulate plasma levels of GLP-1 through two main mechanisms: (i) sequestration of locally produced gut GLP-1, limiting its entry into the blood/circulation, and (ii) altered GLP-1 production through the formation of new L-cells. Altogether, the authors present a model whereby IELs control GLP-1 bioavailability, demonstrating that gut T-cells can participate in incretin hormone control of metabolism.

These findings demonstrate one way that resident gut immune cells can influence whole body metabolism by regulating local intestinal hormone production and systemic bioavailability of an integrin. Intriguingly, the authors show that αβ and γδ intraepithelial T-cells can act as a local sink to capture gut GLP-1. Immune cell sequestration of locally produced hormones is another factor to consider in GLP-1 therapies. However, further investigation is warranted because β7 deletion, but not GLP-1R deletion, in IELs appears to be the key factor in controlling systemic levels of GLP-1. Yusta et al. (4) previously showed that GLP-1R^−/− mice have compromised intestinal barrier function, suggesting that receptor-mediated binding of GLP-1 in IELs could be involved in a complex network of factors that regulate incretin synthesis and production. Because IELs inhabit predominantly the small intestine, ingested dietary antigens may also affect the function of these lymphocytes. Additionally, the contribution of each T-cell subset in regulating GLP-1 bioavailability also requires further clarification. Resident IELs vs peripheral T-cell subsets may have divergent sensing and effector functions in response to various nutrient or bacterial antigens.

Because specific factors derived from gut bacteria can alter GLP-1 levels, the authors assessed the contribution of gut microbes to the metabolic phenotype in β7^−/− mice. Results from antibiotic treatment and cohousing experiments suggest that these approaches do not reveal a substantial bacterial contribution to the metabolic benefits in β7^−/− mice. These findings do not completely rule out the microbiota’s involvement in IELs’ regulation of GLP-1. In β7^−/− mice, these methods to manipulate the microbiota were not sufficient to reveal control of GLP-1 bioavailability by IELs. However, in the context of functional β7 integrin and diet-induced metabolic disease, it is possible that gut microbes relay signals that shape the enteric T-cell profile (5). In fact, it has been previously shown that GLP-1R^−/− mice have altered intestinal microbiome composition (4). GLP-1 levels are influenced by microbial-derived metabolites, including short chain fatty acids and secondary bile acids (6, 7), but it remains to be determined whether IELs relay microbial signals into altered GLP-1 responses. It is possible that bidirectional communication involving specific microbial metabolites, bacterial components (such as lipopolysaccharides or cell wall muropeptides), and signals from T-cells themselves influence GLP-1 bioavailability by altering the number of T-cells that express a high level of cell surface GLP-1R (GLP-1R^high) or fine tuning of GLP-1R expression in intestinal T-cells.

IELs are now positioned as immunometabolism sentinels that can relay gut sensing and local immune responses to systemic changes in metabolism. Greater understanding of the triggers and mechanisms underpinning IEL regulation of GLP-1 bioavailability could influence the efficacy and timing of GLP-1R agonist treatments as they potentially move from injectable to oral drugs (8).

Glossary

Abbreviations:

GLP-1

glucagon-like peptide 1

GLP-1R

glucagon-like peptide 1 receptor

IEL

intraepithelial T-cell