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Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue.

Alcaide P, Jones TG, Lord GM, Glimcher LH, Hallgren J, Arinobu Y, Akashi K, Paterson AM, Gurish MA, Luscinskas FW - J. Exp. Med. (2007)

Bottom Line: Surprisingly, we found that MCp homing to the lung or small intestine in T-bet(-/-) mice is reduced.MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing.Nonetheless, T-bet(-/-) mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function.

View Article: PubMed Central - PubMed

Affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
The transcription factor T-bet was identified in CD4(+) T cells, and it controls interferon gamma production and T helper type 1 cell differentiation. T-bet is expressed in certain other leukocytes, and we recently showed (Lord, G.M., R.M. Rao, H. Choe, B.M. Sullivan, A.H. Lichtman, F.W. Luscinskas, and L.H. Glimcher. 2005. Blood. 106:3432-3439) that it regulates T cell trafficking. We examined whether T-bet influences homing of mast cell progenitors (MCp) to peripheral tissues. Surprisingly, we found that MCp homing to the lung or small intestine in T-bet(-/-) mice is reduced. This is reproduced in adhesion studies using bone marrow-derived MCs (BMMCs) from T-bet(-/-) mice, which showed diminished adhesion to mucosal addresin cellular adhesion molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1), endothelial ligands required for MCp intestinal homing. MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing. However, adoptive transfer experiments revealed that T-bet expression by BM cells is required for MCp homing to the intestine. Furthermore, transfer of WT BM-derived dendritic cells (DCs) to T-bet(-/-) mice restores normal MCp intestinal homing in vivo and MCp adhesion to MAdCAM-1 and VCAM-1 in vitro. Nonetheless, T-bet(-/-) mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function. Therefore, remarkably, T-bet expression by DCs indirectly controls MCp homing to mucosal tissues.

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Tissue MCp reconstitution in SIBR BALB/c mice receiving T-bet−/− or WT BM and in SIBR T-bet−/− mice receiving WT BM. (A) Total number of MCp in the intestine, the BM (one femur), and the spleen in SIBR BALB/c mice receiving BALB/c BM (shaded bars) or T-bet−/− BM (open bars) were assessed in parallel by a MCp limiting dilution assay. Values are the mean ± SEM of five separate experiments. **, P < 0.001 relative to WT BM reconstituted mice. (B) Total number of MCp in the intestine, the BM, and the spleen in SIBR T-bet mice receiving WT BM (open bars). SIBR WT mice receiving WT BM were used as controls (shaded bars) and evaluated in parallel as in A. Values are the mean ± SEM of three separate experiments.
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fig5: Tissue MCp reconstitution in SIBR BALB/c mice receiving T-bet−/− or WT BM and in SIBR T-bet−/− mice receiving WT BM. (A) Total number of MCp in the intestine, the BM (one femur), and the spleen in SIBR BALB/c mice receiving BALB/c BM (shaded bars) or T-bet−/− BM (open bars) were assessed in parallel by a MCp limiting dilution assay. Values are the mean ± SEM of five separate experiments. **, P < 0.001 relative to WT BM reconstituted mice. (B) Total number of MCp in the intestine, the BM, and the spleen in SIBR T-bet mice receiving WT BM (open bars). SIBR WT mice receiving WT BM were used as controls (shaded bars) and evaluated in parallel as in A. Values are the mean ± SEM of three separate experiments.

Mentions: In view of the inability of our assays to detect T-bet expression in MCp or cultured BMMCs, we were forced by the observed striking defect of MCp pools in certain mucosal tissues of T-bet– mice to pursue other approaches to understanding how T-bet exerts this effect. To define whether the observed homing defect was due exclusively to a defect in the T-bet−/− BM (including MCp or other BM precursors expressing T-bet) or, alternatively, to a defect of the local intestinal microenvironment by itself, we depleted the hematopoietic precursors in WT mice by sublethal irradiation and then reconstituted the animals by adoptive transfer of either WT or T-bet−/− BM cells (SIBR). The number of MCp found in the intestine of WT-SIBR mice reconstituted with T-bet−/− BM was very low compared with that in WT-SIBR mice reconstituted with WT BM. In contrast, the numbers of MCp in the spleen and BM were not significantly different in WT mice reconstituted with T bet−/− BM from those reconstituted with WT BM. (Fig. 5 A). On the other hand, sublethally irradiated T-bet−/− mice reconstituted with BM from WT mice showed total reconstitution of intestinal MCp, as well as of BM and spleen MCp (Fig. 5 B). These results demonstrate that the MCp that arise from the T bet−/− BM show a defect in homing to the intestine despite normal numbers of precursors in the spleen or BM, whereas the MCp arising from the WT BM and transferred into a T-bet−/− host show adequate tissue homing of MCp, including homing to the intestine. These data implicate a defect or loss of T-bet–expressing cells in the BM compartment that is responsible for the lack of MCp adhesion and intestinal-specific homing in the T-bet−/− mice and rule out the possibility of a defect in the intestinal compartment of T-bet−/− mice.


Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue.

Alcaide P, Jones TG, Lord GM, Glimcher LH, Hallgren J, Arinobu Y, Akashi K, Paterson AM, Gurish MA, Luscinskas FW - J. Exp. Med. (2007)

Tissue MCp reconstitution in SIBR BALB/c mice receiving T-bet−/− or WT BM and in SIBR T-bet−/− mice receiving WT BM. (A) Total number of MCp in the intestine, the BM (one femur), and the spleen in SIBR BALB/c mice receiving BALB/c BM (shaded bars) or T-bet−/− BM (open bars) were assessed in parallel by a MCp limiting dilution assay. Values are the mean ± SEM of five separate experiments. **, P < 0.001 relative to WT BM reconstituted mice. (B) Total number of MCp in the intestine, the BM, and the spleen in SIBR T-bet mice receiving WT BM (open bars). SIBR WT mice receiving WT BM were used as controls (shaded bars) and evaluated in parallel as in A. Values are the mean ± SEM of three separate experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2118716&req=5

fig5: Tissue MCp reconstitution in SIBR BALB/c mice receiving T-bet−/− or WT BM and in SIBR T-bet−/− mice receiving WT BM. (A) Total number of MCp in the intestine, the BM (one femur), and the spleen in SIBR BALB/c mice receiving BALB/c BM (shaded bars) or T-bet−/− BM (open bars) were assessed in parallel by a MCp limiting dilution assay. Values are the mean ± SEM of five separate experiments. **, P < 0.001 relative to WT BM reconstituted mice. (B) Total number of MCp in the intestine, the BM, and the spleen in SIBR T-bet mice receiving WT BM (open bars). SIBR WT mice receiving WT BM were used as controls (shaded bars) and evaluated in parallel as in A. Values are the mean ± SEM of three separate experiments.
Mentions: In view of the inability of our assays to detect T-bet expression in MCp or cultured BMMCs, we were forced by the observed striking defect of MCp pools in certain mucosal tissues of T-bet– mice to pursue other approaches to understanding how T-bet exerts this effect. To define whether the observed homing defect was due exclusively to a defect in the T-bet−/− BM (including MCp or other BM precursors expressing T-bet) or, alternatively, to a defect of the local intestinal microenvironment by itself, we depleted the hematopoietic precursors in WT mice by sublethal irradiation and then reconstituted the animals by adoptive transfer of either WT or T-bet−/− BM cells (SIBR). The number of MCp found in the intestine of WT-SIBR mice reconstituted with T-bet−/− BM was very low compared with that in WT-SIBR mice reconstituted with WT BM. In contrast, the numbers of MCp in the spleen and BM were not significantly different in WT mice reconstituted with T bet−/− BM from those reconstituted with WT BM. (Fig. 5 A). On the other hand, sublethally irradiated T-bet−/− mice reconstituted with BM from WT mice showed total reconstitution of intestinal MCp, as well as of BM and spleen MCp (Fig. 5 B). These results demonstrate that the MCp that arise from the T bet−/− BM show a defect in homing to the intestine despite normal numbers of precursors in the spleen or BM, whereas the MCp arising from the WT BM and transferred into a T-bet−/− host show adequate tissue homing of MCp, including homing to the intestine. These data implicate a defect or loss of T-bet–expressing cells in the BM compartment that is responsible for the lack of MCp adhesion and intestinal-specific homing in the T-bet−/− mice and rule out the possibility of a defect in the intestinal compartment of T-bet−/− mice.

Bottom Line: Surprisingly, we found that MCp homing to the lung or small intestine in T-bet(-/-) mice is reduced.MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing.Nonetheless, T-bet(-/-) mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function.

View Article: PubMed Central - PubMed

Affiliation: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
The transcription factor T-bet was identified in CD4(+) T cells, and it controls interferon gamma production and T helper type 1 cell differentiation. T-bet is expressed in certain other leukocytes, and we recently showed (Lord, G.M., R.M. Rao, H. Choe, B.M. Sullivan, A.H. Lichtman, F.W. Luscinskas, and L.H. Glimcher. 2005. Blood. 106:3432-3439) that it regulates T cell trafficking. We examined whether T-bet influences homing of mast cell progenitors (MCp) to peripheral tissues. Surprisingly, we found that MCp homing to the lung or small intestine in T-bet(-/-) mice is reduced. This is reproduced in adhesion studies using bone marrow-derived MCs (BMMCs) from T-bet(-/-) mice, which showed diminished adhesion to mucosal addresin cellular adhesion molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1), endothelial ligands required for MCp intestinal homing. MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing. However, adoptive transfer experiments revealed that T-bet expression by BM cells is required for MCp homing to the intestine. Furthermore, transfer of WT BM-derived dendritic cells (DCs) to T-bet(-/-) mice restores normal MCp intestinal homing in vivo and MCp adhesion to MAdCAM-1 and VCAM-1 in vitro. Nonetheless, T-bet(-/-) mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function. Therefore, remarkably, T-bet expression by DCs indirectly controls MCp homing to mucosal tissues.

Show MeSH
Related in: MedlinePlus