M Cells

Abstract

The mucosal immune system in the gastrointestinal tract helps protect against orally acquired pathogens. To efficiently do this, the mucosal immune system must be able to sample the gut lumenal contents to enable it to generate protective immune responses against pathogens. The transport of luminal antigens across mucosal epithelia is a key initial step in the induction of an efficient mucosal immune response. Here, we discuss how a unique population of epithelial cells termed M cells (or ‘microfold’ cells) enables the mucosal immune system to efficiently sample the intestinal contents. We describe the characteristic features of M cells; describe the molecular and cellular factors that influence their differentiation and functional maturation; discuss how lumenal antigens are sampled by M cells and also how the specific targeting of antigens to M cells may represent a novel method to induce antigen‐specific mucosal immunity.

Key Concepts

  • The mucosal immune system in the gastrointestinal and respiratory tracts acts to protect against pathogens acquired by ingestion and inhalation, respectively.
  • The transport of luminal antigens across mucosal epithelia is a key initial step in the induction of an efficient mucosal immune response.
  • M cells are a unique population of epithelial cells which are specialised for the transcytosis of a broad range of materials such as particulate antigens, soluble macromolecules, pathogens and secretory IgA across the gut epithelium into the gut‐associated lymphoid tissues.
  • The efficient transcytosis of antigens by M cells is an important first step in the induction of efficient mucosal immune responses to certain pathogenic microorganisms.
  • M cells derive from Lgr5+ stem cells in the intestinal crypts.
  • Stimulation via the cytokine RANKL and the subsequent intrinsic expression of distinct transcription factors specifically trigger the differentiation of the Lgr5+ stem‐cell‐derived proliferative daughter cells into mature, functional M cells.
  • The sampling of lumenal antigens by M cells may occur in a nonselective manner (e.g. via constitutive micropinocytosis). However, M cells also appear to express a range of ‘immunosurveillance’ receptors suggesting that some antigens are acquired specifically via receptor‐mediated endocytosis.
  • The specific targeting of vaccine antigens may represent novel strategies to develop mucosal vaccines and induce mucosal immunity.
  • Aging has a dramatic influence on the functional maturation of M cells.

Keywords: M cells; gut‐associated lymphoid tissues (GALT); mucosal immune system; intestine; Peyer's patches

Figure 1. The microarchitecture of Peyer's patches in the small intestine. (a) Gut‐associated lymphoid tissues such as Peyer's patches contain B‐cell follicles (green upper panel). A homogenous population of mononuclear phagocytes expressing CD11c (red, upper panel), CSF1R (green, middle panel) and CD68 (green, lower panel) accumulate within the subepithelial dome (SED) region and are positioned to sample antigens which have been transcytosed across the specialised follicle‐associated epithelium (FAE). The boundary of the FAE is indicated by the broken lines. V, villi. (b) En‐face whole‐mount micrograph of a Peyer's patch of a mouse. Two FAE are visible. M cells (GP2+ cells, green) are a unique population of epithelial cells which are situated within the FAE and are specialised for the transcytosis of a broad range of particulate antigens across the gut epithelium into the gut‐associated lymphoid tissues. M cells are rarely found within the surrounding villi (V). The specimen is counterstained with the lectin UEA‐1 to detect mucus‐producing goblet cells (red).
Figure 2. The basolateral pocket beneath the M‐cell contains mononuclear phagocytes (MNP). En‐face whole‐mount micrograph of a Peyer's patch showing the presence of CSF1R‐expressing MNP (cyan) in the follicle‐associated epithelium (FAE) within the basolateral pocket beneath the M cells (GP2+ cells, red). Following their uptake, antigens are rapidly transcytosed and released into the intraepithelial pocket beneath the M cell's basolateral membrane. This specialised microenvironment enables close interactions between the M cells and MNP. The boundary of the FAE is indicated by the broken line. V, villi.
Figure 3. Important factors which influence the differentiation and functional maturation of M cells in the gut‐associated lymphoid tissues. (a) The dome‐associated crypts surrounding the follicle‐associated epithelium (FAE) contain stem cells which produce highly proliferative daughter cells (Ki67+ proliferating cells, green). The boundary of the crypt is indicated. (b) These stem cells express Lgr5 and are nestled between Paneth cells (lysozyme‐expressing cells, red). It is not possible to detect Lgr5 by immunohistochemistry; expression of OLFM4 is used here as a surrogate marker for Lgr5+ cells (green). (c) In the intestine, RANKL is selectively expressed in the GALT by networks of subepithelial dome (SED) stromal cells (green). RANKL is the critical cytokine that directs the differentiation of enterocytes into M cells. V, villi. (d) The subsequent maturation of the differentiating cells into functionally mature M cells is regulated by their intrinsic expression of the RANKL‐induced ETS transcription factor Spi‐B (green, arrows). (e) High levels of the chemokine CCL20 (red) are specifically expressed by the FAE. Interactions between CCR6‐expressing B cells and the FAE appear to provide additional stimulation which promotes the functional maturation of M cells.
Figure 4. The density of M cells is dramatically reduced in the follicle‐associated epithelium (FAE) overlying Peyer's patches in aged mice (∼600 days old). En‐face whole‐mount micrograph of Peyer's patches from young (a) and aged (b) mice. Tissues were immunostained to detect GP2+ M cells (green) and goblet cells (UEA‐1‐binding cells, red).
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Mabbott, Neil A, Sehgal, Anuj, and Donaldson, David S(Sep 2015) M Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026239]