In vivo exit of c-kit+/CD49dhi/β7+ mucosal mast cell precursors from the bone marrow following infection with the intestinal nematode Trichinella spiralis

Abstract

We have used the parasite helminth Trichinella spiralis to study the generation and differentiation of mast cell progenitors in the bone marrow of mice, as this infection triggers an intestinal mastocytosis which correlates with parasite expulsion. C-kit ؉ mast cell progenitors have previously been defined by methylcellulose colony-forming units and by limiting dilution assays in vitro. In vivo experiments have demonstrated the essential requirement by mast cells for specific integrin expression. We have defined 2 c-kit ؉ populations in the bone marrow, one of which coexpresses CD49d/␤7 integrin, a marker essential for small intestine immigration. We have confirmed the phenotype of these cells by using antagonistic anti-c-kit antibody in vivo. Our data show that the loss of c-kit ؉ /␤7 ؉ cells from the bone marrow correlates with their appearance in the blood and precedes detection of mature mast cells in the gut by 3 days. This exit correlates with an increase in soluble stem cell factor (SCF) in the serum, suggesting that the c-kit/SCF interaction may be chemotactic or haptotactic in nature. This study shows that during infection the bone marrow environment generates mast cells destined for the intestinal mucosa before their exit into the periphery, indicating a clear interplay between infection site and hematopoietic tissue. IntroductionThe existence of mast cell progenitors (MCp's) in various tissues has been clearly demonstrated by in vitro culture and limiting dilution assays, 1-3 although isolation and phenotypic analysis of these cells ex vivo has been more elusive. It was not until 1996 that a committed precursor for the mast cell lineage was first identified in mouse fetal blood, using c-kit (stem cell factor receptor) as a surface marker. 4 c-kit is unique in that it is expressed on primitive and pluripotent stem cells, then subsequently retained by committed MCp's, making the latter presently more identifiable by their response to growth factors in vitro than by their expression of particular cell surface markers. Moreover, few studies in vivo have investigated early mast cell differentiation under conditions of infectious challenge and have largely concentrated on their steadystate production. This lack of investigation is particularly surprising, because a major role for mast cells is in mediating responses to antigenic and infectious challenge.Trichinella spiralis is a gut-dwelling nematode which causes intestinal hyperplasia and mastocytosis. Because this correlates well with worm expulsion, 5-7 we are interested in understanding the generation of mast cells to dissect the mechanisms governing the resolution of infection. Previous work with bone marrow chimeras 8 has shown that mast cell deficiency in W/W v mice is primarily a hematopoietic and not a lymphopoietic defect. 6 Limiting dilution assays have defined resting mast cell progenitor populations in many different tissues, including small and large intestine, lung, spleen, and bone marrow. 3 It is possible to adoptively transfer a high prod...

Integrin αIIbβ3 Induces the Adhesion and Activation of Mast Cells through Interaction with Fibrinogen

“…1, A and B), both of which were Ͼ90% Fc⑀RI ϩ /c-kit ϩ using flow cytometric analysis. We confirmed the expression of integrin ␣ 4 (11,13,30,46,47), ␣ 5 (5,11,26,28,30), ␣ V (12), ␣ L (48, 49), ␤ 1 (11,26), ␤ 2 (50), and ␤ 3 (12), as reported (Fig. 1A).…”

“…Accumulating evidence revealed that several kinds of integrins were involved in the migration of mast cells (13,37,47,50), and that the interaction between SCF and c-kit regulated the migration of mast cells via ECM proteins, especially FN (13, 14, 37, 47, 50, 52). We examined SCF-induced migration of mast cells via fibrinogen, and then tested whether integrin ␣ IIb ␤ 3 -fibrinogen interaction would induce migration.…”

Clonogenic mast cell progenitors and their excess numbers in chimeric BALB/c mice with inactivated GATA-1

“…In view of the dependency of GATA-1 Plt13/ϩ mast cells on stimulation by the combination of SCF and IL-3 and the absence of IL-3 in unmanipulated mice (17), the injection of IL-3 might similarly increase mast cell numbers in the Plt13 spleen-the spleen being the most responsive to IL-3 stimulation of mast cell numbers (18). There would also be merit in examining the allelic type of tissue mast cells developing in Plt13 mice in response to worm infestation (19,20) to establish whether GATA-1 Plt13 mast cells were able to take part in such responses.…”

Mast cells, which interact with Escherichia coli, up-regulate genes associated with innate immunity and become less responsive to FcεRI-mediated activation

“…6). In the mouse, CD40d mediates mast cell adhesion to endothelium and is important for mast cell immigration into the small intestine during nematode infection [36]. huMC up-regulated genes involved in antigen presentation such as CD80 (Fig.…”