γδ T cells regulate the intestinal response to nutrient sensing

γδ T cells link immunity to nutrition

Gamma delta (γδ) T cells are immune cells best known for host barrier defenses in epithelial tissues. Sullivan et al. discovered a previously unrecognized role for γδ T cells in sensing nutrient uptake in the small intestine (see the Perspective by Talbot and Littman). The researchers analyzed mice fed a high-carbohydrate versus a high-protein diet and observed remodeling of the small intestinal epithelium in response to dietary carbohydrates. Nutrient availability triggered an epithelial–immune cell circuit that was required for digestion and absorption of carbohydrates. Intestinal γδ T cells regulated the expression of a carbohydrate transcriptional program by limiting interleukin-22 production from type 3 innate lymphoid cells. These findings may also provide insights into how γδ T cells modulate metabolic disease.

Science, this issue p. eaba8310; see also p. 1202

Structured Abstract


The gastrointestinal (GI) tract is a multikingdom cellular ecosystem that facilitates the procurement of nutrients from the environment. In constant contact with the external world, the small intestine is at once a gateway for life-threatening pathogens and toxins and the site of absorption for life-sustaining nutrients. Consequently, this tissue is tasked with the challenge of balancing its primary functions of nutrient uptake and host defense in response to a complex and constantly changing environment.

This challenge is particularly daunting for omnivores, whose diets change on daily, seasonal, and developmental time scales. The diverse diets of such generalists stand in contrast to those of specialists—animals that consume restricted diets—such as carnivores and herbivores. Whereas these specialists have evolved fixed morphologic adaptations in the organization of the GI tract that facilitate efficient nutrient uptake from their restricted diets, generalists must constantly adapt to the shifting availability of food sources of diverse nutrient composition encountered throughout life. These ongoing changes in diet exist alongside encounters with ingested toxins, enteric pathogens, and commensal microbes. Omnivorous lifestyles therefore require that the GI tracts of such animals dynamically adapt to the changes in availability of different nutrients. We examined the molecular and cellular mechanisms that regulate intestinal adaptation to diverse foods.


We investigated how the enzymes and transporters involved in the digestion and absorption of macronutrients are regulated in response to diet. We designed special animal diets that differed only in the ratio of protein to carbohydrates and evaluated gene expression changes in the GI tract, as well as systemic metabolism, after feeding these diets to mice. Recent discoveries pertaining to intestinal defenses against parasitic and microbial pathogens have demonstrated that interactions between intestinal epithelial cells and lymphocytes—the largest population of lymphocytes in the body—coordinate tissue responses to enteric infection. Guided by these findings, we hypothesized that the regulation of nutrient-handling machinery may involve coordination between tissue-resident lymphocytes and intestinal epithelial cells. Furthermore, recent work investigating mechanisms of host defense in this tissue led us to hypothesize that cellular remodeling of the intestinal epithelium, which occurs in response to certain infections, may also underlie its adaptation to different nutrients.


A carbohydrate transcriptional program comprising enzymes and transporters that mediate the digestion and absorption of carbohydrates was induced on demand in small-intestine epithelial cells in response to carbohydrate availability. The induction of this transcriptional program was specifically due to the availability of carbohydrates and reflected functional changes in nutrient handling at the tissue and systemic levels. Mice fed a high-carbohydrate diet exhibited changes in the frequency of specialized enterocyte subsets. This indicated that functional specialization exists within the enterocyte compartment, which constitutes approximately 80% of the intestinal epithelium. This also suggested that the induction of the carbohydrate transcriptional program involved cellular remodeling of the intestinal epithelium. The induction of this program and corresponding epithelial remodeling occurred rapidly, after only 5 days of high-carbohydrate feeding. Unexpectedly, the on-demand induction of this program required γδ T cells, a population of lymphocytes enriched at barrier surfaces whose biology remains poorly understood. Intestinal γδ T cells were altered by diet, with changes observed in their transcriptome, tissue localization, and behavior. The diet-dependent regulation of this program by γδ T cells involved suppression of a negative regulator, interleukin-22 (IL-22). Thus, we defined an epithelial-lymphocyte circuit that regulates the intestinal response to nutrient sensing and facilitates the adaptation to diverse diets.


Our work demonstrates a role for intestinal lymphocytes in regulating the tissue response to dietary nutrients. Together with other studies in the realm of host-pathogen interactions, our results indicate that lymphocyte-epithelial circuits and epithelial remodeling represent general features of how the intestine adapts to environmental change. By linking nutrition and barrier function at both the cellular and molecular levels, these adaptations allow this complex tissue to adjust the balance between nutrient uptake and host defense in response to environmental change.

Lymphocyte-epithelial interactions mediate intestinal adaptation to environmental change.

The small intestine adjusts the balance between host defense and nutrient uptake in response to environmental signals, including the availability of nutrients and presence of pathogens. The ability of this tissue to adjust the balance between its primary functions in response to environmental cues is mediated through cellular remodeling of the epithelium and lymphocyte-epithelial circuits.


The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The “on-demand” induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing.

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