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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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Histochemical analysis of tissue sections prepared from the intestine and spleen of WT and T-bet−/− mice. (A) Sections of small intestine or spleen from WT or T-bet−/− BALB/c mice were incubated with chloroacetate esterase substrate to identify MCs (indicated by the arrows). 1 representative field out of 20 fields analyzed per mouse is shown. Bar, 200 μm. (B) Quantification of MCs per cross section of tissue. Values are the mean ± SEM for three BALB/c and four T-bet−/− mice and are the total number of MCs per cross section of jejunum or spleen. *, P < 0.05.
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fig2: Histochemical analysis of tissue sections prepared from the intestine and spleen of WT and T-bet−/− mice. (A) Sections of small intestine or spleen from WT or T-bet−/− BALB/c mice were incubated with chloroacetate esterase substrate to identify MCs (indicated by the arrows). 1 representative field out of 20 fields analyzed per mouse is shown. Bar, 200 μm. (B) Quantification of MCs per cross section of tissue. Values are the mean ± SEM for three BALB/c and four T-bet−/− mice and are the total number of MCs per cross section of jejunum or spleen. *, P < 0.05.

Mentions: We have recently shown that CD4+ T cell trafficking in T-bet−/− mice is dramatically reduced (20). Our interest in MC trafficking then led us to investigate whether MCp homing to the mucosal tissues is impaired in T-bet−/− mice. We measured the total number of MCp in the intestine and the lung, as well as in the BM and the spleen. T-bet deficiency resulted in a nearly total loss of the MCp reservoir normally present in the small intestine and in a significant decrease in the lung, whereas MCp numbers in the spleen and the BM were comparable to those in WT mice. This finding was consistently observed in both BALB/c (Fig. 1 A) and C57BL/6 (Fig. 1 B) mice strains lacking T-bet. Consistent with previous findings (13), the number of MCp found in the tissues examined in the BALB/c strain was greater than that in C57/BL6 mice. Histochemical analysis of tissue sections prepared from intestine and spleen of adult, age-matched T-bet−/− and WT mice also showed that fewer MCs were detected in the intestine of T bet−/− compared with WT mice. In the spleen, which showed no differences in MCp, MCs were also diminished in the T-bet−/− mice (Fig. 2). These data indicate that under basal conditions in the absence of T-bet there is a tissue-specific homing defect in MCp homing to mucosal tissues.


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)

Histochemical analysis of tissue sections prepared from the intestine and spleen of WT and T-bet−/− mice. (A) Sections of small intestine or spleen from WT or T-bet−/− BALB/c mice were incubated with chloroacetate esterase substrate to identify MCs (indicated by the arrows). 1 representative field out of 20 fields analyzed per mouse is shown. Bar, 200 μm. (B) Quantification of MCs per cross section of tissue. Values are the mean ± SEM for three BALB/c and four T-bet−/− mice and are the total number of MCs per cross section of jejunum or spleen. *, P < 0.05.
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Related In: Results  -  Collection

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fig2: Histochemical analysis of tissue sections prepared from the intestine and spleen of WT and T-bet−/− mice. (A) Sections of small intestine or spleen from WT or T-bet−/− BALB/c mice were incubated with chloroacetate esterase substrate to identify MCs (indicated by the arrows). 1 representative field out of 20 fields analyzed per mouse is shown. Bar, 200 μm. (B) Quantification of MCs per cross section of tissue. Values are the mean ± SEM for three BALB/c and four T-bet−/− mice and are the total number of MCs per cross section of jejunum or spleen. *, P < 0.05.
Mentions: We have recently shown that CD4+ T cell trafficking in T-bet−/− mice is dramatically reduced (20). Our interest in MC trafficking then led us to investigate whether MCp homing to the mucosal tissues is impaired in T-bet−/− mice. We measured the total number of MCp in the intestine and the lung, as well as in the BM and the spleen. T-bet deficiency resulted in a nearly total loss of the MCp reservoir normally present in the small intestine and in a significant decrease in the lung, whereas MCp numbers in the spleen and the BM were comparable to those in WT mice. This finding was consistently observed in both BALB/c (Fig. 1 A) and C57BL/6 (Fig. 1 B) mice strains lacking T-bet. Consistent with previous findings (13), the number of MCp found in the tissues examined in the BALB/c strain was greater than that in C57/BL6 mice. Histochemical analysis of tissue sections prepared from intestine and spleen of adult, age-matched T-bet−/− and WT mice also showed that fewer MCs were detected in the intestine of T bet−/− compared with WT mice. In the spleen, which showed no differences in MCp, MCs were also diminished in the T-bet−/− mice (Fig. 2). These data indicate that under basal conditions in the absence of T-bet there is a tissue-specific homing defect in MCp homing to mucosal tissues.

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