Publications by Year: 2025

Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis^1,2. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule β (RELMβ)^3,4 is a critical regulator of oral tolerance. RELMβ is abundant in the sera of both patients with FA and mouse models of FA. Deletion of RELMβ protects mice from FA and the development of food-antigen-specific IgE and anaphylaxis. RELMβ disrupts food tolerance through the modulation of the gut microbiome and depletion of indole-metabolite-producing Lactobacilli and Alistipes. Tolerance is maintained by the local production of indole derivatives driving FA protective RORγt⁺ regulatory T (T_reg) cells⁵ through activation of the aryl hydrocarbon receptor. RELMβ antagonism in the peri-weaning period restores oral tolerance and protects genetically prone offspring from developing FA later in life. Together, we show that RELMβ mediates a gut immune–epithelial circuit regulating tolerance to food antigens—a novel mode of innate control of adaptive immunity through microbiome editing—and identify targetable candidates in this circuit for prevention and treatment of FA.

Enteroendocrine cells (EECs) of the intestinal epithelium are major regulators of metabolism and energy homeostasis. This is mainly due to their expression and secretion of enteroendocrine peptides (EEPs). These peptides serve as hormones that control many aspects of metabolic homeostasis including feeding behavior, intestinal contractions, and utilization of energy stores. Regulation of EEP production and release depends largely on EEC-exclusive G protein-coupled receptors (GPCRs) that sense nutrient levels. Here we report the characterization of a GPCR expressed principally in EECs, which we have named GulpR due to its role in the response to nutrient stress. We show that GulpR regulates transcription of the EEP Tachykinin (Tk) and that both GulpR and Tk are essential for the transcriptional response that promotes survival of nutrient limitation. Oral infection with V. cholerae also activates expression of GulpR, Tk, and lipid mobilization genes. However, Tk does not play a role in regulation of lipid mobilization genes during infection and does not impact survival. Our findings identify a role for GulpR and Tk in survival during starvation and suggest that, although starvation and infection result in significant mobilization of energy stores, the signal transduction systems that regulate the metabolic response to each are distinct.

Regulatory T cells (Tregs) are central to immune homeostasis and controlling inflammation through multiple mechanisms, however, recent discoveries and advances in technology reveal that Tregs exert a diverse array of functions beyond mere immunosuppression, adapting uniquely to the specialized environments of tissues. This review delves into the multifaceted, tissue-specific mechanisms of Tregs, highlighting their roles in tissue repair, inflammatory modulation, and tolerance maintenance. We explore the developmental, functional, and metabolic pathways that drive Treg specialization across distinct organs, such as the central nervous system, gastrointestinal tract, joints, skin, and lungs, and examine how these insights advance the design of novel, targeted therapies for autoimmune and inflammatory disorders. This review will emphasize non-suppressive functions, discussing how Tregs can be harnessed in therapeutic applications tailored to specific tissue microenvironments, offering a promising new direction for the treatment of autoimmune diseases.