Human Gut ‘Gatekeeper’ Cells Found to Present Gluten Directly to the Immune System

New findings reshape understanding of celiac disease initiation

Scientists have identified a previously unrecognized role for specialized cells in the human gut, revealing that microfold (M) cells do more than transport material from the intestine’s lumen into underlying immune tissues. These cells can also directly present gluten antigens to the immune system, a discovery that may reshape current models of how celiac disease begins and progresses.

In a study using advanced human intestinal organoid models, researchers showed that M cells in the gut epithelium not only ferry antigens to immune cells but also behave much like dendritic cells, a key type of professional antigen-presenting cell. By expressing major histocompatibility complex class II (MHC-II) molecules and sharing a gene expression profile with lymphoid dendritic cells, human M cells appear to serve as an unexpected frontline interface between dietary proteins and the adaptive immune system.

The findings offer fresh insight into why individuals with genetic risk factors for celiac disease might develop an aggressive immune response to gluten, a protein complex found in wheat, barley, and rye. They also highlight potential new therapeutic targets aimed at modulating how the gut initially handles dietary antigens.

From transporters to active immune players

M cells are specialized epithelial cells that sit atop Peyer’s patches — organized lymphoid structures embedded in the small intestine that monitor gut contents and coordinate immune responses. Historically, M cells have been described as transporters: they sample microorganisms, particles, and antigenic material from the intestinal lumen and deliver them across the epithelium to underlying immune cells, such as dendritic cells, B cells, and macrophages.

Until now, their role was largely framed as passive conduits. Antigen presentation, especially the activation of naïve CD4+ T cells, was thought to be handled mainly by hematopoietic cells like dendritic cells and macrophages residing beneath the epithelial barrier.

The new study challenges this division of labor. Using human-derived intestinal organoids — miniaturized, three-dimensional structures grown from stem cells that reproduce many features of the gut — the researchers were able to reconstruct the full developmental trajectory of M cells in vitro and profile their molecular features in detail.

What they found is that human M cells:

• Express MHC-II molecules at baseline, even without inflammatory conditions.
• Share hallmark gene expression signatures with lymphoid dendritic cells, including CD83, LAMP3, and IL7R.
• Possess specialized compartments that appear optimized for antigen processing and presentation.

This combination of properties indicates that M cells act as non-hematopoietic antigen-presenting cells within Peyer’s patches, effectively blurring the line between epithelial barrier cells and classic immune cells.

A developmental pathway guided by SPIB, RUNX2, RANKL, and CSF2

To understand how M cells acquire their immune-like behavior, the researchers reconstructed their differentiation pathway from intestinal stem cells using organoid models. The developmental process appears to be staged and tightly regulated by specific transcription factors and signaling molecules.

Key findings include:

• M cells progress through distinct differentiation stages defined by the transcription factors SPIB and RUNX2.
• Their development is driven by signals from RANKL (receptor activator of nuclear factor kappa-Β ligand) and CSF2 (colony-stimulating factor 2), both of which are involved in immune and bone biology.
• As these transcriptional programs unfold, M cells progressively acquire the genetic and functional hallmarks associated with antigen uptake, processing, and presentation.

By mapping these stages, the study provides a framework for understanding how M cells become specialized gatekeepers of intestinal immunity. It also offers potential molecular targets for therapies aimed at altering M cell behavior in conditions such as celiac disease, food allergy, or inflammatory bowel disorders.

MHC-II expression sets M cells apart from enterocytes

A central element of the discovery concerns MHC-II expression. In the gut, enterocytes — the main absorptive epithelial cells — generally do not express MHC-II under normal conditions. They can be induced to do so in the presence of inflammatory signals, especially interferon-gamma, which is abundant during infections or chronic inflammation.

In contrast, the study shows that human M cells:

• Constitutively express MHC-II molecules, even in the absence of inflammatory cytokines.
• Organize MHC-II within specialized antigen-processing compartments, suggesting a built-in capability to capture, modify, and present antigens to CD4+ T cells.

This constitutive expression means that M cells are ready by default to interact with T cells and present antigens, including components of the diet. In practical terms, that could allow the immune system to detect and respond to dietary proteins earlier and more directly than previously appreciated, which may be beneficial for defense against pathogens but problematic when the target is a harmless food antigen such as gluten.

Gluten processing and T cell activation in celiac risk donors

To probe the relevance of these findings to celiac disease, the researchers performed co-culture experiments using organoids and immune cells derived from individuals carrying the HLA-DQ2.5 allele. This genetic variant, one of the strongest known risk factors for celiac disease, encodes an MHC-II molecule that binds deamidated gluten peptides with high affinity.

In these assays, M cells were exposed to gluten peptides under controlled conditions. The study found that:

• M cells efficiently internalized gluten peptides from the luminal side.
• Once internalized, gluten was processed through transglutaminase 2 (TG2)-mediated deamidation, a modification known to increase peptide binding to HLA-DQ2.5 and enhance immunogenicity.
• Processed gluten peptides were presented on MHC-II molecules on the surface of M cells.
• Gluten-specific CD4+ T cells in co-culture became activated, proliferated, and upregulated activation markers.

These results indicate that M cells themselves can carry out the crucial sequence of steps that transforms dietary gluten into a potent antigen capable of stimulating T cells. This process has traditionally been attributed to dendritic cells sampling gluten fragments transported across the epithelium, but the new data suggest that part of this work begins within the epithelial layer itself.

Rethinking early events in celiac disease

Celiac disease is a chronic autoimmune disorder triggered by gluten in genetically susceptible individuals. It leads to inflammation and damage of the small intestinal mucosa, resulting in symptoms ranging from diarrhea and abdominal pain to anemia, weight loss, and nutrient deficiencies. The only current treatment is a strict, lifelong gluten-free diet.

Previous models of celiac disease initiation have emphasized:

• Gluten uptake through the intestinal barrier, possibly via paracellular leakage or epithelial transport.
• Antigen capture and processing by dendritic cells in the lamina propria or Peyer’s patches.
• Presentation of deamidated gluten peptides on HLA-DQ2.5 or HLA-DQ8 molecules to CD4+ T cells.
• Subsequent B cell activation, antibody production, and tissue damage.

The new findings suggest that M cells may play a more central role at the earliest stage of this cascade. Because they can both transport and present gluten peptides directly within Peyer’s patches, M cells could:

• Provide an efficient route for naïve T cells to first encounter gluten antigens.
• Initiate immune responses in the absence of overt inflammation, due to their constitutive MHC-II expression.
• Shape the quality and strength of the T cell response, potentially tipping the balance between tolerance and autoimmunity.

This mechanism may help explain why some individuals with genetic susceptibility develop celiac disease while others remain tolerant despite similar gluten exposure, depending on how M cells sample and present these antigens.

Historical context: from hidden villi damage to molecular mechanisms

Understanding of celiac disease has evolved dramatically over the past century. In the mid-20th century, clinicians linked childhood malabsorption syndromes to dietary wheat and introduced gluten-free diets as therapy. Subsequent decades saw the characterization of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis as hallmark intestinal lesions.

The identification of HLA-DQ2 and HLA-DQ8 as major genetic risk factors established celiac disease as a strongly immune-mediated disorder. The discovery that tissue transglutaminase is both the main autoantigen and a key enzyme that modifies gluten peptides further clarified the autoimmune component.

More recently, research has focused on:

• How gluten crosses the intestinal barrier.
• How innate and adaptive immune responses interact in the gut mucosa.
• The role of gut microbiota and environmental factors in modulating disease risk.

The new evidence that M cells resemble dendritic cells and act as direct antigen-presenting cells adds another layer to this history. It moves the frontier of understanding farther upstream, to the very first moments when gluten meets the immune system at the intestinal surface.

Economic and healthcare impact of improved understanding

Celiac disease carries a significant economic and healthcare burden globally. Diagnosis often requires endoscopy, biopsies, and specialized serologic testing, while long-term management depends on access to gluten-free foods, nutritional counseling, and ongoing monitoring for complications such as osteoporosis or associated autoimmune conditions.

Better knowledge of early disease mechanisms could have several practical implications:

• Development of therapies that modulate M cell function, aiming to reduce harmful gluten presentation or promote tolerance.
• Creation of targeted drugs that interfere with TG2-mediated deamidation in M cells.
• Novel vaccines or oral tolerance strategies designed to act at the level of Peyer’s patches and the epithelium.

If such approaches reduce the need for invasive procedures, hospital visits, or strict dietary restrictions, they could lower healthcare costs and improve quality of life for patients. They may also benefit the large number of individuals who remain undiagnosed but symptomatic, a group that represents a hidden economic burden through reduced productivity and increased use of general healthcare services.

Regional comparisons and global relevance

The impact of these findings may vary across regions with different dietary patterns, genetic backgrounds, and healthcare infrastructures. Celiac disease is most commonly diagnosed in Europe, North America, and parts of South America and Oceania, where wheat-based diets are prevalent and genetic risk alleles such as HLA-DQ2.5 are relatively common.

However, recognition of celiac disease is rising in regions such as the Middle East, North Africa, South Asia, and Latin America, where wheat consumption has increased due to urbanization and changing food systems. In many of these areas, diagnostic infrastructure and awareness remain limited, contributing to underdiagnosis and delays in treatment.

A deeper understanding of M cell biology could inform:

• Population-specific research into how local genetics and diets affect M cell-mediated antigen presentation.
• Strategies to prevent disease in high-risk families identified by genetic screening.
• Public health efforts that balance the benefits of wheat-based staples with awareness of gluten-related disorders.

Although the new study focuses on gluten and celiac disease, the implications extend to other conditions involving breakdowns in oral tolerance, including some food allergies and inflammatory bowel diseases, which also show regional differences in prevalence and severity.

Future directions: targeting the epithelial-immune interface

The recognition that M cells act as non-hematopoietic antigen-presenting cells opens several avenues for future research and therapeutic innovation. Potential next steps include:

• Investigating how M cell numbers and function differ between healthy individuals and patients with active or treated celiac disease.
• Exploring whether modifying RANKL, CSF2, SPIB, or RUNX2 signaling can safely alter M cell differentiation and antigen-presenting capacity.
• Studying how infections, microbiota composition, and dietary patterns influence M cell behavior and MHC-II expression.
• Assessing whether similar antigen-presenting roles exist for M cells in other mucosal tissues, such as the respiratory tract.

For now, the discovery reinforces the idea that the intestinal epithelium is not just a passive barrier but an active participant in immune surveillance. In the case of celiac disease, that participation may begin earlier and more directly than previously thought, with M cells acting as crucial gatekeepers that decide whether gluten remains a food or becomes a trigger for autoimmunity.