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. 2012 May;136(1):86-95.
doi: 10.1111/j.1365-2567.2012.03562.x.

Natural killer T cells suppress zymosan A-mediated granuloma formation in the liver by modulating interferon-γ and interleukin-10

Takahiro Kobayashi  1 , Hiroki Kawamura, Yasuhiro Kanda, Hiroaki Matsumoto, Suguru Saito, Kazuyoshi Takeda, Toshihiko Kawamura, Toru Abo
Affiliations

Natural killer T cells suppress zymosan A-mediated granuloma formation in the liver by modulating interferon-γ and interleukin-10

Takahiro Kobayashi et al. Immunology. 2012 May.

Abstract

Wild-type (WT) and CD1d(-/-) [without natural killer (NK) T cells] mice were treated with zymosan A to induce granuloma formation in the liver. Increased granuloma formation was seen in NKT-less mice on days 7 and 14 after administration. WT mice showed limited granuloma formation, and zymosan A eventually induced NKT cell accumulation as identified by their surface marker (e.g. CD1d-tetramer). Zymosan A augmented the expression of Toll-like receptor 2 on the cell surface of both macrophages and NKT cells. One possible reason for accelerated granuloma formation in NKT-less mice was increased production of interferon- γ (IFN-γ); a theory that was confirmed using IFN-γ(-/-) mice. Also, zymosan A increased interleukin-10 production in WT mice, which suppresses IFN-γ production. Taken together, these results suggest that NKT cells in the liver have the potential to suppress zymosan A-mediated granuloma formation.

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Figures

Figure 1
Figure 1
Granuloma formation in the livers of wild-type (WT) and CD1d−/− [natural killer T (NKT) cell-less] mice. (a) The number of mononuclear cells in the liver. (b) The number of granulomas in the liver. (c) Histology. WT and NKT-less mice were treated with zymosan A and various parameters were examined at the indicated time-points. Data represent the mean ± SD from four mice. **P < 0·01.
Figure 2
Figure 2
Identification of natural killer T (NKT) cells and macrophages. (a) Two-colour staining for CD3 and CD1d-tetramer. (b) Number of NKT cells. (c) Two-colour staining for Mac-1 and Gr-1. (d) Number of macrophages. (e) Identification of NKT cells in CD1d−/− mice. Mononuclear cells were isolated from the livers of wild-type (WT) and NKT-less mice. Immunofluorescence studies were done to identify NKT cells (CD3int CD1d-tetramer+) and macrophages (Gr-1int Mac-1+). The data represent the mean ± SD from four mice. **P < 0·01.
Figure 3
Figure 3
Expression of Toll-like receptor 2 (TLR2) on natural killer T (NKT) cells and macrophages. Wild-type (WT) mice were treated with zymosan A and mononuclear cells were isolated from the liver on the indicated days. Three-colour staining for TLR2, NK1.1 (or Gr-1) and CD3 (or Mac-1) was then performed. To show the expression of TLR2, the gated analysis was conducted for NKT cells (NK1.1+ CD3int), macrophages (Gr-1int Mac-1+), and T cells (NK1.1− CD3high). Representative results from three independent experiments are shown. The numbers in the figure represent the percentage of fluorescence-positive cells.
Figure 4
Figure 4
Interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) production in wild-type (WT) and CD1d−/− mice. (a) IFN-γ and TNF-α levels in the sera. (b) IFN-γ and TNF-α levels in the culture supernatants. (c) Cytoplasmic detection of IFN-γ and TNF-α in different leucocyte populations. Cytoplasmic cytokines were detected using immunofluorescence. Data represent the mean ± SD from four experiments.
Figure 5
Figure 5
Association of interferon-γ (IFN-γ) with granuloma formation. (a) Liver histology. (b) Number of granulomas. Wild-type (WT), CD1d−/− and IFN-γ−/− mice were treated with zymosan A. On the indicated days, hepatic tissue was isolated. The data represent the mean ± SD of the number of granulomas in four mice. *P < 0·05 and **P < 0·01.
Figure 6
Figure 6
Increased interleukin-10 (IL-10) production in wild-type (WT) mice. (a) IL-10 levels in sera. (b) IL-10 mRNA expression. (c) Real-time PCR. RNA was isolated from concanavalin A (Con A) blasts and lipopolysaccharide (LPS) blasts were used as a positive control. Data represent the mean ± SD IL-10 concentration in the sera of four mice. For experiment (b), representative results are shown. *P < 0·05.
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