M Cells: Gatekeepers of Intestinal Immunity

The immune system must defend against harmful pathogens while tolerating beneficial microbes and nutrients. In the intestine, specialized microfold (M) cells play a crucial role by sampling antigens from the gut lumen and delivering them to underlying immune cells.

Understanding M cells is essential because they influence both protective immunity and susceptibility to infections or inflammatory diseases. Their ability to transport antigens makes them central to mucosal defense, vaccine responses, and interactions with gut microbiota.

Tissue Distribution and Morphology

M cells are primarily located in the follicle-associated epithelium (FAE) of Peyer’s patches in the small intestine and the mucosa-associated lymphoid tissue (MALT) of the colon. These regions, rich in immune structures, facilitate antigen sampling. While Peyer’s patches are the most well-characterized locations, M cells are also found in nasopharyngeal-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT), though their density and function vary by tissue environment. Their distribution is highest where immune surveillance is most active.

Structurally, M cells differ from neighboring enterocytes. Unlike absorptive epithelial cells, which have a dense brush border of microvilli, M cells possess a sparse and irregular microfolded surface that facilitates direct interaction with luminal contents. Beneath the apical surface, they form an intraepithelial pocket housing dendritic cells, macrophages, and lymphocytes, enabling rapid antigen transfer to the immune system.

M cells exhibit a distinct cytoskeletal organization, with reduced expression of proteins like villin and ezrin, which maintain the rigid microvillar structure of enterocytes. Instead, they rely on a flexible actin network that supports antigen transport. Additionally, they express glycoproteins and adhesion molecules that enhance bacterial and particulate antigen capture.

Mechanisms of Antigen Uptake

M cells internalize and transport antigens from the intestinal lumen through specialized processes. Unlike enterocytes, which focus on nutrient absorption, M cells lack digestive enzymes and have a reduced glycocalyx, allowing direct interaction with microbial and particulate antigens. Glycoproteins such as GP2 serve as key recognition molecules, binding bacterial fimbriae and directing pathogens toward endocytosis. Studies show GP2 specifically interacts with type I pili-expressing bacteria like Escherichia coli and Salmonella, promoting antigen capture.

Once bound, antigens are internalized through phagocytosis, macropinocytosis, and receptor-mediated endocytosis. Unlike classical phagocytes, M cells do not degrade internalized material but rapidly shuttle it through a transcytotic pathway. Vesicular trafficking bypasses lysosomal degradation, preserving antigen integrity. Early endosomes transport antigens across the cytoplasm, where vesicles migrate to the basolateral membrane and release their contents into the intraepithelial pocket.

M cells express high levels of β1 integrins, which interact with microbial adhesins to facilitate internalization. Pathogens like Yersinia enterocolitica exploit β1 integrins to gain entry, leveraging this pathway to establish infection. Similarly, commensal bacteria use these interactions to access deeper mucosal layers. Particulate antigens such as vaccines and nanoparticles are selectively taken up through this pathway, positioning M cells as key mediators of mucosal immunization.

Role in Mucosal Immunity

M cells shape immune surveillance by transporting antigens across the epithelial barrier, allowing continuous sampling of microbial and dietary components. This selective antigen transfer maintains immune homeostasis, ensuring immune cells receive a controlled influx of external stimuli. M cell density and function fluctuate in response to environmental factors like diet, microbiota composition, and inflammation.

Once antigens reach underlying immune structures, antigen-presenting cells process them to guide immune responses. Dendritic cells in the intraepithelial pocket capture and present antigens to naïve T cells, determining whether a response will be tolerogenic or inflammatory. The ability of M cells to deliver intact antigens is particularly relevant for mucosal vaccines. Experimental models show that increasing M cell density in the follicle-associated epithelium improves vaccine uptake, underscoring their role in immunization strategies.

Differentiation and Development

M cell formation is a tightly regulated process driven by intrinsic genetic programming and extrinsic signaling cues. Unlike enterocytes, which follow a default differentiation pathway, M cell development requires specific molecular signals that reprogram precursor cells. The transcription factor Spi-B is essential, governing the transition from undifferentiated progenitors to antigen-transporting cells. Deletion of Spi-B results in a complete absence of M cells in Peyer’s patches, highlighting its role in lineage specification.

Signaling interactions between epithelial progenitors and stromal cells further influence differentiation. RANKL, a member of the tumor necrosis factor (TNF) superfamily, is secreted by stromal cells underlying Peyer’s patches and binds to RANK on epithelial precursors, triggering Spi-B activation. Studies in mice show that administering exogenous RANKL induces M cell differentiation in intestinal regions that typically lack them, demonstrating the potency of this signaling axis.

Interactions With Gut Microbiota

M cells continuously interact with gut microbiota, influencing microbial composition and immune responses. Certain beneficial microbes use M cells to reach immune structures, conditioning immune responses and reinforcing mucosal tolerance. For example, segmented filamentous bacteria (SFB) use M cells to access Peyer’s patches, stimulating Th17 cell differentiation, which is essential for gut homeostasis.

Pathogenic microbes, however, exploit M cell transcytosis to breach the epithelial barrier. Bacteria such as Salmonella enterica and Yersinia pseudotuberculosis use specialized adhesins to target M cell receptors, facilitating entry into underlying tissues. This ability to bypass epithelial defenses makes M cells an entry point for infection. Factors like diet, antibiotics, and host genetics influence M cell density and function. Research suggests that modulating M cell activity through dietary components or probiotics could help steer gut microbiota composition toward a beneficial state.

M Cell Dysfunctions and Related Conditions

Disruptions in M cell function can significantly impact intestinal health. Deficiencies in M cell development, often linked to impaired RANKL signaling or Spi-B mutations, reduce antigen sampling and compromise immune surveillance. This defect is observed in conditions like Crohn’s disease, where altered M cell density correlates with dysregulated immune responses. Inflammatory cytokines can further modify M cell morphology, impairing antigen translocation and exacerbating mucosal inflammation.

M cell dysfunction also affects susceptibility to infections. A reduction in functional M cells limits protective immune priming, increasing the risk of enteric bacterial infections. Conversely, excessive M cell activity may enhance pathogen uptake, facilitating systemic bacterial dissemination. Research into therapeutic interventions targeting M cell regulation, such as controlled RANKL stimulation or microbiota-based modulation, holds promise for correcting these imbalances. Understanding M cells’ role in disease progression may provide new avenues for preventive and therapeutic strategies.