M cells, gatekeepers or gateway to the gut

Glycoprotein 2 is the M cell receptor for type I pili on bacteria and is important for the immune response to these bacteria, according to research by Hase and colleagues published last week in the journal Nature.

The mucosal immune system is one of the largest components of our immune system and is hugely important for protecting mucosal surfaces (like our gastrointestinal tract) from harmful pathogens. Our guts are home to trillions of commensal bacteria which live quite happily there causing us no harm whatsoever. The gastrointestinal tract is protected from these bacteria (or other damaging substances) by a layer of tightly packed epithelial cells which form a barrier against any bacteria or molecules penetrating the gut. However, Microfold (M) cells are specialised intestinal cells located over mucosal lymphoid tissue called Peyer’s patches which are potential entry points into the host. M cells sample microorganisms or molecules in our gut and help transport them across the epithelial cell barrier (a process called antigen transcytosis) to deliver to professional immune cells (like macrophages, T cells or dendritic cells) to stimulate a protective immune response. In essence, M cells act like CCTV cameras to survey the gut area for anything that is out of the ordinary, or potentially harmful, and then present them to our immune system (essentially the police and the law courts) to sort those bad ‘uns out.

Previous work had shown that antigen transcytosis by M cells is important for mucosal immune responses but little was known about the mechanism involved. The researchers used microarray to scan the entire genome for specific molecules associated with M cells and found that glycoprotein 2 (GP2) was expressed in M cells in both human and mouse Peyer’s patches. Using immunoelectron microscopy they showed that GP2 was localised to the apical surface of M cells (the surface exposed to the commensal bacteria in the gut). Furthermore, they found that GP2 bound a variety of commensal and pathogenic enterobacteria (Escherichia coli, Salmonella enterica serovar Enteritidis and Salmonella Typhimurium), and more specifically bound to FimH expressed in the bacterial type I pilus (filamentous projections on the bacterial surface which are important for adhesion). Three-dimensional imaging revealed that GP2 accumulates around E. coli and S. Typhimurium as they are internalised in M cells and deletion of GP2 in mice reduced the uptake of type-I-piliated bacteria. After bacteria are translocated through M cells in a GP2-dependent manner they were captured by dendritic cells. Furthermore, GP2 was important for induction of mucosal immune responses against specific bacterial antigens (proteins that stimulate an immune response). Bacteria deficient in FimH lost the ability to bind GP2, had reduced entry into Peyer’s patches and induced a weak helper T cell and antibody immune response. Similarly, mice lacking GP2 had reduced helper T cell and antibody immune responses after challenge with bacteria expressing FimH.

This paper highlights the biological importance of GP2-dependent M cell antigen transcytosis as part of immunosurveillance in the intestine for bacteria expressing FimH. More work is needed to fully understand exactly what happens to the bacteria after they are delivered to immune cells and tissues by the M cells. Finally, M cells are thought to be a promising target for oral vaccinations to induce a protective immune response and this work shows that GP2 may be a possible vaccine target.

Although M cells act as a great surveillance system for the gut there are always a few bacteria that abuse the system. Shigella is one particular deviant bacterium that cannot normally invade the apical surface of intestinal epithelial cells and so uses the M cells to breach the epithelial cell barrier and gain access to their basolateral surface. Here, they can successfully invade, replicate in the intestinal epithelium, and wreak havoc on the gut by causing shigellosis or bacillary dysentery.

Hase, K., Kawano, K., Nochi, T., Pontes, G., Fukuda, S., Ebisawa, M., Kadokura, K., Tobe, T., Fujimura, Y., Kawano, S., Yabashi, A., Waguri, S., Nakato, G., Kimura, S., Murakami, T., Iimura, M., Hamura, K., Fukuoka, S., Lowe, A., Itoh, K., Kiyono, H., & Ohno, H. (2009). Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response Nature, 462 (7270), 226-230 DOI: 10.1038/nature08529

Further reading

Jang, M.H. et al., (2004) Intestinal villous M cells: An antigen entry site in the mucosal epithelium. Proceedings of the National Academy of Sciences, 101, p.6110-6115.

Schroeder, G.N. and Hilbi, H. (2008) Molecular pathogenesis of Shigella spp.: Controlling host cell signalling, invasion and death by Type III secretion. Clinical Reviews Microbiology, 21, p.134-156.