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Dickkopf-3, a tissue-derived modulator of local T-cell responses.

Meister M, Papatriantafyllou M, Nordström V, Kumar V, Ludwig J, Lui KO, Boyd AS, Popovic ZV, Fleming TH, Moldenhauer G, Nawroth PP, Gröne HJ, Waldmann H, Oelert T, Arnold B - Front Immunol (2015)

Bottom Line: While T-cell development and activation status in naïve Dkk3-deficient mice was comparable to littermate controls, we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T-cell-mediated rejection.In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism.Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4(+) and CD8(+) T-cell responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.

ABSTRACT
The adaptive immune system protects organisms from harmful environmental insults. In parallel, regulatory mechanisms control immune responses in order to assure preservation of organ integrity. Yet, molecules involved in the control of T-cell responses in peripheral tissues are poorly characterized. Here, we investigated the function of Dickkopf-3 in the modulation of local T-cell reactivity. Dkk3 is a secreted, mainly tissue-derived protein with highest expression in organs considered as immune-privileged such as the eye, embryo, placenta, and brain. While T-cell development and activation status in naïve Dkk3-deficient mice was comparable to littermate controls, we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T-cell-mediated rejection. Moreover, genetic deletion or antibody-mediated neutralization of Dkk3 led to an exacerbated experimental autoimmune encephalomyelitis (EAE). This phenotype was accompanied by a change of T-cell polarization displayed by an increase of IFNγ-producing T cells within the central nervous system. In the wild-type situation, Dkk3 expression in the brain was up-regulated during the course of EAE in an IFNγ-dependent manner. In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism. Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4(+) and CD8(+) T-cell responses.

No MeSH data available.


Related in: MedlinePlus

Increased proportions of CD4+ CD25+ Foxp3+ regulatory T cells and IL-17-producing CD4+ T cells in the CNS but not in the draining lymph nodes (Figure 6H) of Dkk3−/− at the peak of EAE. (A) EAE was induced in Dkk3−/− and WT mice by immunization with MOG33–55 in CFA. Mean clinical EAE score over time is displayed. At the indicated time point (black arrow, 14 days after EAE induction), half of the mice were sacrificed and lymphocytes were isolated from brain and spinal cord for analysis in (B–G) (n = 8). (B) Percentages of CD4+ and CD8+ T cells among leukocytes in the CNS of Dkk3−/− and WT mice. (C) Proportion of CD25+ Foxp3+ of CD4+ cells (*p < 0.05). (D–G) Isolated lymphocytes from (A) were re-stimulated in vitro with 50 μg/ml MOG33–55 peptide for 6 h in the presence of Golgi Plug and intracellularly stained for the respective cytokines. Shown is one representative dot plot (left panel) and cumulative data of three individual experiments (n = 8). (D) Percentages of IL-17+ of CD4+ T cells (*p < 0.05). (E) Percentages of GM-CSF+ of CD4+ T cells. (F) Percentages of IFNγ+ of CD4+ T cells. (G) Percentages of IFNγ+ of CD8+ T cells. (H) Percentages of CD4+ and CD8+ T cells in spleen and peripheral lymph nodes (LN) of respective mice from (A). (I) Percentages of CD25+ Foxp3+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A). (J) Percentages of IL-17+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A).
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Figure 5: Increased proportions of CD4+ CD25+ Foxp3+ regulatory T cells and IL-17-producing CD4+ T cells in the CNS but not in the draining lymph nodes (Figure 6H) of Dkk3−/− at the peak of EAE. (A) EAE was induced in Dkk3−/− and WT mice by immunization with MOG33–55 in CFA. Mean clinical EAE score over time is displayed. At the indicated time point (black arrow, 14 days after EAE induction), half of the mice were sacrificed and lymphocytes were isolated from brain and spinal cord for analysis in (B–G) (n = 8). (B) Percentages of CD4+ and CD8+ T cells among leukocytes in the CNS of Dkk3−/− and WT mice. (C) Proportion of CD25+ Foxp3+ of CD4+ cells (*p < 0.05). (D–G) Isolated lymphocytes from (A) were re-stimulated in vitro with 50 μg/ml MOG33–55 peptide for 6 h in the presence of Golgi Plug and intracellularly stained for the respective cytokines. Shown is one representative dot plot (left panel) and cumulative data of three individual experiments (n = 8). (D) Percentages of IL-17+ of CD4+ T cells (*p < 0.05). (E) Percentages of GM-CSF+ of CD4+ T cells. (F) Percentages of IFNγ+ of CD4+ T cells. (G) Percentages of IFNγ+ of CD8+ T cells. (H) Percentages of CD4+ and CD8+ T cells in spleen and peripheral lymph nodes (LN) of respective mice from (A). (I) Percentages of CD25+ Foxp3+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A). (J) Percentages of IL-17+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A).

Mentions: At the peak of the disease, when EAE symptoms in Dkk3−/− and WT mice were still comparable (Figure 5A), the numbers of infiltrating CD4+ and CD8+ T cells in the CNS were similar (Figure 5B). However, while GM-CSF and IFNγ producing cells were not affected (Figures 5E–G), the proportion of IL-17-producing CD4+ T cells was slightly increased in the CNS of Dkk3-deficient mice (Figure 5D). Interestingly, at the same time, the proportion of CD4+ CD25+ Foxp3+ regulatory T cells was significantly elevated (Figure 5C). These differences were absent in spleen and draining lymph nodes (Figures 5H–J) indicating a local effect of Dkk3.


Dickkopf-3, a tissue-derived modulator of local T-cell responses.

Meister M, Papatriantafyllou M, Nordström V, Kumar V, Ludwig J, Lui KO, Boyd AS, Popovic ZV, Fleming TH, Moldenhauer G, Nawroth PP, Gröne HJ, Waldmann H, Oelert T, Arnold B - Front Immunol (2015)

Increased proportions of CD4+ CD25+ Foxp3+ regulatory T cells and IL-17-producing CD4+ T cells in the CNS but not in the draining lymph nodes (Figure 6H) of Dkk3−/− at the peak of EAE. (A) EAE was induced in Dkk3−/− and WT mice by immunization with MOG33–55 in CFA. Mean clinical EAE score over time is displayed. At the indicated time point (black arrow, 14 days after EAE induction), half of the mice were sacrificed and lymphocytes were isolated from brain and spinal cord for analysis in (B–G) (n = 8). (B) Percentages of CD4+ and CD8+ T cells among leukocytes in the CNS of Dkk3−/− and WT mice. (C) Proportion of CD25+ Foxp3+ of CD4+ cells (*p < 0.05). (D–G) Isolated lymphocytes from (A) were re-stimulated in vitro with 50 μg/ml MOG33–55 peptide for 6 h in the presence of Golgi Plug and intracellularly stained for the respective cytokines. Shown is one representative dot plot (left panel) and cumulative data of three individual experiments (n = 8). (D) Percentages of IL-17+ of CD4+ T cells (*p < 0.05). (E) Percentages of GM-CSF+ of CD4+ T cells. (F) Percentages of IFNγ+ of CD4+ T cells. (G) Percentages of IFNγ+ of CD8+ T cells. (H) Percentages of CD4+ and CD8+ T cells in spleen and peripheral lymph nodes (LN) of respective mice from (A). (I) Percentages of CD25+ Foxp3+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A). (J) Percentages of IL-17+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A).
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Related In: Results  -  Collection

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Show All Figures
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Figure 5: Increased proportions of CD4+ CD25+ Foxp3+ regulatory T cells and IL-17-producing CD4+ T cells in the CNS but not in the draining lymph nodes (Figure 6H) of Dkk3−/− at the peak of EAE. (A) EAE was induced in Dkk3−/− and WT mice by immunization with MOG33–55 in CFA. Mean clinical EAE score over time is displayed. At the indicated time point (black arrow, 14 days after EAE induction), half of the mice were sacrificed and lymphocytes were isolated from brain and spinal cord for analysis in (B–G) (n = 8). (B) Percentages of CD4+ and CD8+ T cells among leukocytes in the CNS of Dkk3−/− and WT mice. (C) Proportion of CD25+ Foxp3+ of CD4+ cells (*p < 0.05). (D–G) Isolated lymphocytes from (A) were re-stimulated in vitro with 50 μg/ml MOG33–55 peptide for 6 h in the presence of Golgi Plug and intracellularly stained for the respective cytokines. Shown is one representative dot plot (left panel) and cumulative data of three individual experiments (n = 8). (D) Percentages of IL-17+ of CD4+ T cells (*p < 0.05). (E) Percentages of GM-CSF+ of CD4+ T cells. (F) Percentages of IFNγ+ of CD4+ T cells. (G) Percentages of IFNγ+ of CD8+ T cells. (H) Percentages of CD4+ and CD8+ T cells in spleen and peripheral lymph nodes (LN) of respective mice from (A). (I) Percentages of CD25+ Foxp3+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A). (J) Percentages of IL-17+ of CD4+ cells in spleen and draining lymph nodes (LN) of respective mice from (A).
Mentions: At the peak of the disease, when EAE symptoms in Dkk3−/− and WT mice were still comparable (Figure 5A), the numbers of infiltrating CD4+ and CD8+ T cells in the CNS were similar (Figure 5B). However, while GM-CSF and IFNγ producing cells were not affected (Figures 5E–G), the proportion of IL-17-producing CD4+ T cells was slightly increased in the CNS of Dkk3-deficient mice (Figure 5D). Interestingly, at the same time, the proportion of CD4+ CD25+ Foxp3+ regulatory T cells was significantly elevated (Figure 5C). These differences were absent in spleen and draining lymph nodes (Figures 5H–J) indicating a local effect of Dkk3.

Bottom Line: While T-cell development and activation status in naïve Dkk3-deficient mice was comparable to littermate controls, we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T-cell-mediated rejection.In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism.Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4(+) and CD8(+) T-cell responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.

ABSTRACT
The adaptive immune system protects organisms from harmful environmental insults. In parallel, regulatory mechanisms control immune responses in order to assure preservation of organ integrity. Yet, molecules involved in the control of T-cell responses in peripheral tissues are poorly characterized. Here, we investigated the function of Dickkopf-3 in the modulation of local T-cell reactivity. Dkk3 is a secreted, mainly tissue-derived protein with highest expression in organs considered as immune-privileged such as the eye, embryo, placenta, and brain. While T-cell development and activation status in naïve Dkk3-deficient mice was comparable to littermate controls, we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T-cell-mediated rejection. Moreover, genetic deletion or antibody-mediated neutralization of Dkk3 led to an exacerbated experimental autoimmune encephalomyelitis (EAE). This phenotype was accompanied by a change of T-cell polarization displayed by an increase of IFNγ-producing T cells within the central nervous system. In the wild-type situation, Dkk3 expression in the brain was up-regulated during the course of EAE in an IFNγ-dependent manner. In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism. Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4(+) and CD8(+) T-cell responses.

No MeSH data available.


Related in: MedlinePlus