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Comparative Study
. 2007 Feb 19;204(2):431-9.
doi: 10.1084/jem.20060626. Epub 2007 Feb 12.

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

Pilar Alcaide  1 , Tatiana G Jones, Graham M Lord, Laurie H Glimcher, Jenny Hallgren, Yojiro Arinobu, Koichi Akashi, Alison M Paterson, Michael A Gurish, Francis W Luscinskas
Affiliations
Comparative Study

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

Pilar Alcaide et al. J Exp Med. .

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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Figures

Figure 1.
Figure 1.
Selective loss of MCp in intestine and lung of T-bet−/− mice. Total numbers of MCp in the intestine, lung, spleen, and BM (one femur) of WT (shaded bars) and T-bet−/− (open bars) mice were determined by limiting dilution MCp assay. Experiments were performed in the BALB/c (A) or C57BL/6 (B) mouse strains. Values are the mean ± SEM for five separate experiments for BALB/c and two separate experiments for C57BL/6 mice. *, P < 0.01; or **, P < 0.001 for T-bet relative to WT mice.
Figure 2.
Figure 2.
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.
Figure 3.
Figure 3.
BMMCs have a defect in adhesion to VCAM-1 or MAdCAM-1 under conditions of shear flow. BMMCs derived from WT BM (shaded bars) or T-bet−/− BM (open bars) were drawn across immobilized VCAM-1 (A) or MAdCAM-1 (B) across a range of estimated shear stress, and adhesive interactions were recorded. BMMC interactions were determined at the end of each shear stress. Values reflect the total number of adherent and rolling cells over time during the range of shear stress examined. Values are the mean ± SEM from five separate experiments. *, P < 0.05; or **, P < 0.01 for T-bet relative to WT mice.
Figure 4.
Figure 4.
Analysis of T-bet expression in BMMCs and in FACS-sorted MCp and their precursors. (A) BMMCs in vitro derived from WT-BALB/c BM were stimulated as indicated in Materials and methods, and cell lysates were subjected to Western blot analysis for T-bet and β-actin. One representative experiment is shown. (B) Quantitative real-time PCR analysis of mRNA levels of T-bet in FACS-sorted BM MCp, myeloid progenitors, and Th1 cells. Results of real-time PCR are normalized to β-actin and are expressed as the mean ± SEM for two independent experiments. (C) RT-PCR analysis of T-bet mRNA levels in purified progenitor populations; β-actin is also shown as loading control.
Figure 5.
Figure 5.
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.
Figure 6.
Figure 6.
BMDCs induce recovery of T-bet−/− intestinal MCp in vivo and adhesion of T-bet−/− BMMCs to VCAM 1 and MAdCAM 1 under conditions of shear flow in vitro. (A) Total number of MCp in the intestine of WT BALB/c (shaded bars) or T-bet−/− (open bars) mice receiving WT DCs was assessed in parallel by MCp limiting dilution assay. Values are the mean ± SEM of two separate experiments using two mice per group. **, P < 0.01. (B and C) BMMCs derived from WT BM or T-bet BM−/− (shaded bars) mice cultured in the presence or absence of BMDCs (open bars) were drawn across immobilized VCAM-1 (B) or MAdCAM-1 (C) at a shear stress of 0.76 dynes/cm2, and adhesive interactions were recorded. Values reflect the total number of adherent and rolling cells. Values are the mean ± SEM of two separate experiments. **, P < 0.01.
Figure 7.
Figure 7.
Time course of worm rejection and histological analysis of WT and T-bet−/− mice infected with T. spiralis. (A) WT (shaded bars) or T-bet−/− (open bars) mice were infected with 450 worms. Six mice of each strain were analyzed for jejunal worm burden on day 13 after infection. Values are the mean number of worms recovered per mouse ± SEM. The BALB/c (A) and C57/BL6 (B) strains are shown. **, P < 0.01. (C) Histochemical analysis for MCs in the jejunum of noninfected or T. spiralis–infected WT and T-bet−/− mice. One representative field is shown for each condition. MCs are indicated by the arrows. Bar, 200 μm. (D) Quantification of MCs in the jejunum of noninfected or T. spiralis–infected WT and T-bet−/− mice. Y-axis values represent the number of MCs present in 10–16 fields for each condition. **, P < 0.01.
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