Mast cell-orchestrated immunity to pathogens

Abstract

Although mast cells were discovered more than a century ago, their functions beyond their role in allergic responses remained elusive until recently. However, there is a growing appreciation that an important physiological function of these cells is the recognition of pathogens and modulation of appropriate immune responses. Because of their ability to instantly release several pro-inflammatory mediators from intracellular stores and their location at the host-environment interface, mast cells have been shown to be crucial for optimal immune responses during infection. Mast cells seem to exert these effects by altering the inflammatory environment after detection of a pathogen and by mobilizing various immune cells to the site of infection and to draining lymph nodes. Interestingly, the character and timing of these responses can vary depending on the type of pathogen stimulus, location of pathogen recognition and sensitization state of the responding mast cells. Recent studies using mast cell activators as effective vaccine adjuvants show the potential of harnessing these cells to confer protective immunity against microbial pathogens.

Figure 1. Mast cells are strategically located in host peripheral tissues

a | A partially degranulated mast cell is visualized by electron microscopy, releasing granules near a blood vessel in mouse ear tissue activated by topical application of phorbol 12-myristate 13-acetate (PMA). The arrow indicates a granule that seems to be in the process of being released. b | Mouse ear tissue was stained in whole mount for CD31-expressing blood vessels (red) and mast cell granules, using a mast cell-specific fluorescent conjugated probe (green), after topical PMA treatment to activate mast cells. c | PMA-treated mouse ear tissue is stained to visualize LYVE1-expressing lymphatic vessels (blue) and mast cells (green). d | This image depicts tyrosine hydroxylase-expressing neurons (red) in close proximity to activated mast cells in compound 48/80-treated whole mounted bladder. e | Mouse ears were treated with PMA and prepared in whole mount for imaging by staining mast cells (green), CD31-expressing blood vessels (red) and CD11c-expressing dendritic cells (blue). For images in b–d, tissue was imaged at x10 magnification. Owing to whole mount preparation and large depth of field, overlap of stained elements can be seen.

Figure 2. Cellular communication by mast cells promotes host defence

Mast cells ‘communicate’ with various cell types, including immune cells (such as lymphocytes^,,, macrophages, dendritic cells^,,,,– and neutrophils^,,,,,), epithelial cells, smooth muscle cells^, and endothelial cells^,–. These interactions contribute to pathogen surveillance, antipathogen immunity and other mechanisms of eliminating microorganisms from the host. These cellular targets of mast cells are located both in the site of infection and in distant draining lymph nodes. Examples of functional consequences of mast cell communication are shown, as are examples of mast cell mediators that have been shown to contribute to the target cell response. BCR, B cell receptor; CCL5, CC-chemokine ligand 5; IL, interleukin; LT, leukotriene; MCP1, mast cell protease 1; PG, prostaglandin; TCR, T cell receptor; TNF, tumour necrosis factor.

Figure 3. Timing of mast cell responses to pathogens

Mast cells can respond quickly to pathogen challenges owing to the presence of preformed mediators in cytoplasmic granules that can be quickly released at a site of infection through the process of degranulation. Mast cells also begin to produce lipid-derived eicosinoid mediators in the initial minutes of activation, as transcription is not required for these mediators to be converted to an active form. In a second wave of the response, consistent with the processes that are initiated by other cells involved in pathogen surveillance, mast cells begin to release de novo synthesized mediators, including a large number of cytokines — such as tumour necrosis factor (TNF) and interleukin-4 (IL-4) — that are transcribed and translated in response to pathogens. They can also replenish their granules, possibly with altered contents, in response to inflammatory signals. Mast cells are unique in their ability to survive for prolonged periods after activation compared with other innate immune cell types that may begin to die during the contraction of the innate response. Finally, mast cells can survive in the tissues and might proliferate in response to appropriate stimuli.

Figure 4. Cell trafficking responses induced or increased by mast cells

Host control and clearance of invading pathogens requires the mobilization of many cell types, both into the site of infection for effective innate immune responses and into draining lymph nodes to initiate appropriate adaptive immune responses. The diverse and divergent cell types that are recruited into infected sites during various models of pathogenesis as a result of mast cell products collectively show the specificity of mast cell-promoted trafficking responses to individual pathogen challenges. a | After entry of a bacterial pathogen, mast cells can become activated and release products that promote many of the necessary cell trafficking events. In models of bacterial pathogenesis, neutrophils are recruited, which are largely responsible for pathogen clearance. Mast cells also enhance the trafficking of dendritic cells (DCs) through infected tissues by mobilizing the DC precursors from the blood and into infected tissues. The activation of several subclasses of DCs has been shown to occur as a result of mast cell activation during bacterial infections, resulting in enhanced trafficking of these cells from infected sites and into draining lymph nodes to initiate adaptive immune responses. Mast cell-derived particles from exocytosed granules can also flow into the lymphatics and travel to draining lymph nodes, where they promote the retention of lymphocytes during the process of lymph node hypertrophy. b | During infection with parasites, eosinophils, basophils and mast cell precursors have been reported to be recruited into sites of infection, such as in the gut. In addition, there is evidence that mast cells proliferate in parasite infection models. c | In viral infection, mast cell activation can promote the chemotaxis of CD8⁺ T cells and natural killer (NK) cells to the peritoneal cavity or in vitro.

Figure 5. Pathogen-specific sensitization of mast cells enhances immune responses

Tissue-resident mast cells are activated by many pathogens, and their products, through innate receptors and, as a result, promote adaptive immunity by modulating dendritic cell migration and cellular events occurring in distant lymph nodes. In addition, they can also be sensitized with various classes of immunoglobulins through Fc receptors (FcRs), enabling them to support more specific, amplified or quicker responses. This ability of mast cells to bind antigen-specific antibodies may be most crucial in secondary challenges, during chronic infection or in situations where innate recognition of a particular pathogen is not sufficient to initiate strong responses by mast cells. Furthermore, mast cells can replenish their granules after being activated and may alter the production of preformed mediators in response to the inflammatory milieu and the cytokines present there. This might result in a different degranulation response during the secondary challenge than during the initial challenge. IL, interleukin; SCF, stem cell factor.