Christoph S. N. Klose

Inflammation resolution depends on coordinated communication between tissue compartments, yet how the intestinal epithelium shapes its immune microenvironment remains poorly understood. Here, using colonic biopsies from patients with ulcerative colitis (UC) and mouse models enabling tissue-wide visualization of NF-κB activity, we combine single-cell RNA sequencing and secretome analysis to define epithelial communication during colitis. We show that, paradoxically, the NF-κB-driven pro-inflammatory secretome of intestinal epithelial cells (IECs) is essential for recovery and prevents unrestrained inflammation. Mechanistically, epithelial NF-κB promotes CCL22-dependent regulatory T cell (Treg cell) recruitment and promotes a tolerogenic, pro-repair cell state, accompanied by induction of the lipid-metabolism-associated GDPD3 and CCR4. In UC, epithelial NF-κB is not uniformly activated but instead induces a selective pro-inflammatory transcriptional program while repressing targets regulating T cell recruitment. Thus, we identify dynamic epithelial–immune communication and demonstrate a protective IEC NF-κB–Treg cell axis important for resolution of intestinal inflammation.

Red pulp macrophages (RPMs) remove senescent erythrocytes from the circulation and recycle their iron for erythropoiesis. The development of RPMs is guided by signals from the microenvironment, which promote expansion and tissue adaptation through the induction of transcription factors, including Spi-C and PPARγ. Here, we show that infection with the nematode Nippostrongylus brasiliensis or treatment with IL-33 results in the accumulation of activated group 2 innate lymphocytes (ILC2s) in the spleen. ILC2s activated by IL-33 drive the expansion of RPMs by secretion of the effector cytokines IL-4/IL-13 and GM-CSF. By contrast, we show that IL-33 is dispensable for RPM development and function under homeostatic conditions. Overall, our work uncovers a previously unrecognized crosstalk between ILC2s and RPMs during type 2 immune responses.

Type 2 immunity has evolved to protect against worms but becomes harmful when activated during allergic inflammation. Group 2 innate lymphoid cells (ILC2s) drive type 2 responses by rapidly secreting IL-5 and IL-13. The alarmins, IL-25, IL-33, and TSLP activate ILC2s and are linked to allergic diseases. However, how alarmins connect to the transcriptional networks driving type 2 effector functions remains elusive. Here, we performed RNA sequencing of ILC2s deficient in IL-25, IL-33, or TSLP pathway and identified the transcription factor Blimp-1 as an IL-33–regulated gene in ILC2s. While Blimp-1 was dispensable for ILC2 development, this transcription factor was required for type 2 cytokine production, driving eosinophilia or promoting worm expulsion. Blimp-1 deficiency resulted in reduced IRF4 expression, while Irf4-deficient ILC2s showed diminished Blimp-1 and IL-33 receptor expression, revealing a reciprocal Blimp-1–IRF4 circuit downstream of the IL-33 receptor. These findings expose the Blimp-1–IRF4 axis as an alarmin-regulated transcriptional network controlling ILC2 effector functions required for type 2 immunity.

Acquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood, and the effect of adipose tissue loss on intestinal inflammation in AGL remains unclear. Using mass cytometry and single-cell RNA-seq, we observed an oligoclonal expansion of T cells in the periphery and inflamed intestine in a patient with AGL and Crohn’s disease (AGLCD). To explore if loss of adipose tissue triggers lymphoproliferation, we studied lipodystrophic mice as a model for AGL. Unexpectedly, lipodystrophic mice did not show T cell expansion, were protected from colitis, and displayed a defect in the development of proinflammatory T cells, which could be reversed by allogeneic fat transplantations, indicating that clonal T cell expansion in AGLCD is not primarily caused by lipodystrophy. Instead, gene sequencing revealed a T cell–intrinsic de novo neuroblastoma RAS viral oncogene homolog ( NRAS ) mutation, implicating somatic mosaicism as a facilitator of clonal T cell expansion and intestinal inflammation in AGLCD.

Innate lymphoid cells (ILCs) are innate immune cells populating many tissues early in ontogeny. ILCs and T cells share basic transcriptional programs, immune modules, and effector functions. This article focuses on ILC2s, a subset capable of producing an array of type 2 cytokines similar to T helper 2 (Th2) cells. While there is a striking overlap in effector functions between ILC2s and Th2 cells, we discuss the distinguishing features and nonredundant functions of ILC2s in homeostasis and during inflammation. These include the regulation of their effector functions, the kinetics of their response, and their spatial distribution. ILC2s interact with different cell types and maintain crosstalk with nonimmune cells, such as epithelial cells, stromal cells, and neurons. We review how neurons and epithelial cells trigger ILC2 responses and depend on ILC2‐derived cytokines, leading to the concept that expulsion of many gut‐dwelling nematodes is initiated and executed by the intestinal epithelium but strictly requires the type 2 immune response orchestrated by ILC2s.

The nervous and immune systems cooperate to regulate mucosal barrier integrity. Nevertheless, whether enteric neurons establish neuroepithelial interactions to coordinate immunity remains elusive. Here, we identified neuroepithelial interactions that differentially control intestinal type 1 and type 2 immunity. Gut epithelial cells expressed vasoactive intestinal peptide (VIP) receptor 1 (VIPR1), and chemogenetic modulation of enteric VIPergic neurons led to altered epithelial-derived cytokines. Epithelial-intrinsic deletion of Vipr1 resulted in diminished type 1 immunity, including reduced type 1 alarmins and intraepithelial lymphocytes. In contrast, epithelial Vipr1 deficiency led to enhanced type 2 immunity, comprising increased type 2 alarmins, tuft cells and activated group 2 innate lymphoid cells. Disruption of neuroepithelial VIP–VIPR1 interactions resulted in increased susceptibility to invasive bacterial infection, which contrasted with enhanced resistance to parasite infection. Our work identifies a multi-tissue axis that controls type 1 and type 2 immunity, deciphering how neuroepithelial interactions distinctively set gut immunity programs.

Barrier homeostasis relies on a finely tuned interplay between the immune system, epithelial cells and commensal microbiota. Beyond these regulators, the enteric nervous system has recently emerged as a central hub coordinating intestinal immune responses, although its role in epithelial differentiation has remained largely unexplored. Here, we identify a neuroepithelial circuit in which vasoactive intestinal peptide (VIP)-positive enteric neurons act on VIPR1⁺ epithelial stem cells to restrain both their proliferation and secretory lineage differentiation. Disruption of this pathway leads to an expansion of tuft cells, enhanced interleukin (IL)-25 production, activation of group 2 innate lymphoid cells (ILC2s) and induction of a type 2 immune response resembling worm expulsion. This phenotype occurs independently of the microbiota but is modulated by the IL-25R–ILC2–IL-13 axis and dietary solid food intake. Our findings expose the enteric nervous system as a critical regulator of epithelial fate decisions and immune balance, complementing established mechanisms that safeguard barrier integrity and mucosal homeostasis.