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Gut mucosal mast cells. Origin, traffic, and differentiation
Abstract:
Gut mucosal mast cells (MMC), which are nearly absent in normal mice are abundant during nematode infection. In normal mice, study of MMC precursors (MMC-P: cells giving rise to MMC colonies in the presence of IL-3) show that: (a) their frequency, judged by limiting dilution is very high in bone marrow (BM) and gut, and very low in most lymphoid organs and thoracic duct lymph (TDL); (b) gut MMC-P are Thy-1- Lyt-1-2- and are not rapidly replicating; (c) they are the progeny of less differentiated BM MMC-P which are attracted from the blood to the gut mucosa by local factor(s), other than antigen and T cell factors (since normal amounts of gut MMC-P are found in germ-free, nude, and newborn mice). In mice bearing the Wehi 3 tumor (which releases enough IL-3 to produce detectable blood levels) spleen and mesenteric lymph nodes (LN) show increased MMC-P frequency, the greatest increase being in the gut and BM, where numerous differentiated MMC are found. In Nippostrongylus brasiliensis (Nb)-infested mice (known to develop a large, T cell-dependent, gut MMC infiltration), gut MMC-P proliferation is induced by IL-3 released from gut mucosal Thy-1+ Lyt-2- cells, whose in vitro IL-3 release capability is much higher than that of similar cells from normal mice. Both Nb-stimulated T blasts and proliferating MMC-P undergo cyclic traffic, migrating into the TDL and then seeding the whole length of the gut (a process which allows a widespread immune defense after a local antigenic stimulus). Experiments using 2-d interruption of this traffic and fetal gut grafts, suggest that the continuous homing of T blasts back to the gut which leads to permanent Nb-stimulated IL-3 release, is essential for the full maturation of MMC. Transfer experiments in the rat show that TDL circulating MMC-P rapidly mature into MMC when they home back to the Nb-infested gut. It is proposed that gut MMC arise after several stages of progressive differentiation of MMC-P, influenced both by IL-3 and unidentified gut factor(s).
Insights
Gut mucosal mast cells (MMC) precursors migrate to the gut and mature into abundant MMC during nematode infection, a process influenced by IL-3 and local factors. This immune response involves T cell activation and cell trafficking for widespread defense.
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Gut mucosal mast cells (MMC) are scarce in normal mice but increase significantly during nematode infections.
- Mast cell precursors (MMC-P) are abundant in bone marrow and gut, with low frequency in lymphoid organs and thoracic duct lymph (TDL).
- Gut MMC-P are Thy-1- Lyt-1-2- and not rapidly replicating in normal mice.
Purpose of the Study:
- To investigate the origin, migration, and differentiation of gut mucosal mast cells (MMC) and their precursors (MMC-P).
- To understand the role of Interleukin-3 (IL-3) and T cells in MMC development during nematode infection.
- To elucidate the homing mechanisms and maturation process of MMC in the gut mucosa.
Main Methods:
- Limiting dilution assays to determine MMC-P frequency in various tissues.
- Flow cytometry (Thy-1, Lyt-1, Lyt-2 markers) to characterize MMC-P.
- Studies in germ-free, nude, and newborn mice to assess antigen and T cell independence.
- Experiments using tumor-bearing mice (Wehi 3) for IL-3 induction.
- Nematode (Nippostrongylus brasiliensis - Nb) infection models.
- Analysis of cell traffic via thoracic duct lymph (TDL) and fetal gut grafts.
- Transfer experiments in rats.
Main Results:
- MMC-P are attracted from the blood to the gut mucosa by local factors, independent of antigen and T cells.
- IL-3, released by gut mucosal Thy-1+ Lyt-2- cells in Nb-infested mice, induces MMC-P proliferation.
- Nb-stimulated T blasts and MMC-P traffic cyclically into TDL and then seed the gut, facilitating widespread immune defense.
- Continuous homing of T blasts to the gut is essential for full MMC maturation, driven by sustained IL-3 release.
- Circulating TDL MMC-P rapidly mature into MMC upon homing to the Nb-infested gut.
Conclusions:
- Gut MMC arise through progressive differentiation of MMC-P, influenced by IL-3 and local gut factors.
- T cell-dependent IL-3 production and cyclic cell trafficking are crucial for the development and maturation of gut MMC during nematode infection.
- The findings suggest a multi-stage differentiation process for gut MMC, involving both systemic and local regulatory mechanisms.