Article

Plasmacytoid precursor dendritic cells from NOD mice exhibit impaired function: are they a component of diabetes pathogenesis?

Institute for Cellular Therapeutics, University of Louisville, Louisville, Kentucky, USA.
Diabetes (Impact Factor: 7.9). 07/2008; 57(9):2360-70. DOI: 10.2337/db08-0356
Source: PubMed

ABSTRACT Plasmacytoid precursor dendritic cell facilitating cells (p-preDC FCs) play a critical role in facilitation of syngeneic and allogeneic hematopoietic stem cell (HSC) engraftment. Here, we evaluated the phenotype and function of CD8(+)/TCR(-) FCs from NOD mice.
The phenotype of CD8(+)/TCR(-) FCs was analyzed by flow cytometry using sorted FCs from NOD, NOR, or B6 mice. The function of NOD FCs was evaluated by colony-forming cell (CFC) assay in vitro and syngeneic or allogeneic HSC transplantation in vivo.
We report for the first time that NOD FCs are functionally impaired. They fail to facilitate engraftment of syngeneic and allogeneic HSCs in vivo and do not enhance HSC clonogenicity in vitro. NOD FCs contain subpopulations similar to those previously described in B6 FCs, including p-preDC, CD19(+), NK1.1(+)DX5(+), and myeloid cells. However, the CD19(+) and NK1.1(+)DX5(+) subpopulations are significantly decreased in number in NOD FCs compared with disease-resistant controls. Removal of the CD19(+) or NK1.1(+)DX5(+) subpopulations from FCs did not significantly affect facilitation. Notably, Flt3 ligand (FL) treatment of NOD donors expanded FC total in peripheral blood and restored facilitating function in vivo.
These data demonstrate that NOD FCs exhibit significantly impaired function that is reversible, since FL restored production of functional FCs in NOD mice and suggest that FL plays an important role in the regulation and development of FC function. FCs may therefore be linked to diabetes pathogenesis and prevention.

0 Bookmarks
 · 
89 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Increased risk and persistence of infections in diabetic condition is likely associated with defect in the cellular immune responses. We previously showed a decrease in the production of interferon-α (IFN-α) by dendritic cells (DCs) in diabetic subjects. The basal level of IFN-α in splenic plasmacytoid DCs (pDCs) is also lower in diabetic NOD mice compared to pre-diabetic mice. The objective of this study was to analyze the ability of diabetic mice to mobilize innate and CD8+ T cell-mediated immune response to influenza A virus (IAV) with live influenza A/Puerto Rico/8/1934 H1N1 (PR8) strain or with its immunodominant CD8+ T cells epitopes. We found that following immunization with IAV, the level of IFN-α in diabetic mice was increased to the level in pre-diabetic mice. Immunization of NOD mice with the immunodominant IAV PR8 peptide induced clonal expansion of interferon-γ (IFN-γ) producing CD8+ T-cells similar to the response observed in pre-diabetic mice. Thus, diabetic and prediabetic NOD mice have a similar capacity for IFN-α and IFN-γ production by pDCs and CD8+ T-cells, respectively. Therefore, dendritic cell related immune defect in diabetic NOD mice does not impair their capacity to develop effective immune response to IAV. Our results suggest reduced IFN-α production by diabetic human and mouse DCs is not an impediment to an effective immunity to IAV in type 1 diabetic subjects vaccinated with live attenuated influenza vaccine.
    Clinical & Experimental Immunology 02/2015; 179(2):245-55. DOI:10.1111/cei.12462 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The signal transducers and activators of transcription (STAT) family of proteins play a critical role in cytokine signaling required for fine tuning of immune regulation. Previous reports showed that a mutation (L327M) in the Stat5b protein leads to aberrant cytokine signaling in the NOD mice. To further elaborate the role of Stat5b in diabetes, we established a NOD transgenic mouse that over-expresses the wild type Stat5b gene. The incidences of spontaneous diabetes as well as cyclophosphamide-induced diabetes were significantly reduced and delayed in the Stat5b transgenic NOD mice compared to their littermate controls. The total cell numbers of CD4(+) T cells and especially CD8(+) T cells in the spleen and pancreatic lymph node were increased in the Stat5b transgenic NOD mice. Consistent with these findings, CD4(+) and CD8(+) T cells from the Stat5b transgenic NOD mice showed a higher proliferation capacity and up-regulation of multiple cytokines including IL-2, IFN-γ, TNF-α and IL-10 as well as anti-apoptotic gene Bcl-xl. Furthermore, the number and proportion of CD4(+)CD25(+) regulatory T cells were significantly increased in transgenic mice although in vitro suppression ability of the regulatory T-cells was not affected by the transgene. Our results suggest that Stat5b confers protection against diabetes in the NOD mice by regulating the numbers and function of multiple immune cell types, especially by up-regulating CD4(+)CD25(+) regulatory T cells.
    Biochemical and Biophysical Research Communications 07/2012; 424(4):669-74. DOI:10.1016/j.bbrc.2012.06.162 · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CD8+TCR- graft facilitating cells (FC) enhance engraftment of hematopoietic stem cells (HSC) in allogeneic and syngeneic recipients. The mechanisms by which FC promote HSC engraftment and tolerance induction have not been fully elucidated. Here, we provide data to support a critical role for dedicator of cytokinesis 2 (DOCK2) in multiple aspects of FC function. DOCK2-/- FC exhibit compromised facilitative function in vivo as evidenced by the loss of engraftment-enhancing capability for c-Kit+Sca-1+lineage- (KSL) cells, and compromised ability to promote KSL cell homing and lodgment in hematopoietic niche. Deletion of DOCK2 abrogates the ability of FC to induce differentiation of naïve CD4+CD25- T cells into FoxP3+ regulatory T cells and interleukin-10-producing type 1 regulatory T cells in vitro. Moreover, DOCK2-/- FC are unable to promote survival of KSL cells when co-cultured with KSL cells. DOCK2-/- FC also exhibit compromised migration to stroma-derived factor-1 in vitro and impaired homing to the bone marrow in vivo. In conclusion, our results demonstrate that DOCK2 is critical for FC to maintain its immunomodulatory function and exert its trophic effects on KSL cells. These findings may have direct clinical relevance to promote HSC engraftment for treatment of autoimmunity, hemoglobinopathies, and to induce transplantation tolerance. Stem Cells 2014
    Stem Cells 07/2014; 32(10). DOI:10.1002/stem.1780 · 7.70 Impact Factor

Full-text (2 Sources)

Download
42 Downloads
Available from
May 27, 2014