Showing papers by "Toshiaki Ohteki published in 2009"
TL;DR: It is shown that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type IIFN signaling, preserves the self-renewal and multilineage differentiation capacity of HSCs.
Abstract: Type I interferons (IFNs), a family of cytokines, orchestrate numerous biological and cellular processes1, 2, 3. Although it is well known that type I IFNs are essential for establishing the host antiviral state4, their role in hematopoietic homeostasis has not been studied. Here we show that type I IFNs induce proliferation and exhaustion in hematopoietic stem cells (HSCs) and that interferon regulatory factor-2 (IRF2), a transcriptional suppressor of type I IFN signaling5, 6, preserves the self-renewal and multilineage differentiation capacity of HSCs. HSCs were substantially less abundant in the bone marrow of Irf2-/- as compared to Irf2+/- mice. Irf2-/- HSCs showed enhanced cell cycling status and failed to produce hematopoietic cells in competitive repopulation assays, and the reconstituting capacity of Irf2-/- HSCs was restored by disabling type I IFN signaling in these cells. In wild-type mice, injection of poly(I:C), an inducer of type I IFN signaling, or IFN- induced HSC proliferation, and chronic type I IFN signaling further reduced the number of quiescent HSCs. Notably, combined poly(I:C) and 5-fluorouracil (5-FU) treatment allowed exogenous HSC engraftment and hematopoietic reconstitution in WT mice. Our findings provide insight into the molecular basis for the maintenance of HSC quiescence and may lead to improvements in bone marrow transplantation and type I IFN-based therapies for viral infection and cancer.
385 citations
TL;DR: IFN-gamma and IL-17 play no critical role in the development of minor-specific allograft rejection in C57BL/6 mice, indicating the presence of sophisticated rejection mechanisms that are still elusive and cannot be ascribed simply to Th1, -2, or -17.
Abstract: Purpose It has been widely accepted that Th1- and IFN-gamma-mediated immune responses are indispensable for corneal allograft rejection in BALB/c hosts The present study was designed to determine the role of IFN-gamma and IL-17 in the rejection by C57BL/6 hosts, which display high rejection rates Methods MHC-matched or -mismatched corneal allografts were grafted onto IFN-gamma-knockout (GKO), IFN-gamma-receptor-knockout (GRKO), IL-17-knockout (IL-17KO), or wild-type (WT) C57BL/6 hosts Graft fates were assessed clinically and histologically At appropriate time intervals after allografting, RNA was isolated from corneal graft parenchymal and stromal tissues and cervical lymph nodes The cytokine mRNA levels of Th1, -2, and -17 type were analyzed by real-time PCR Results No significantly prolonged allograft survival was observed in any combinations The rejected MHC-mismatched corneas in GKO elicited intensive infiltration of eosinophils, CD11b(+) macrophages, and B cells, but few Gr-1(+)CD11c(-) neutrophils In contrast, rejected MHC-matched corneas in GKO hosts, as well as GRKO and WT hosts, elicited intensive infiltration of CD11b(+) macrophages and Gr-1(+)CD11c(-) neutrophils, but no B220(+) B cells and eosinophils At 1 week after MHC-matched allografting, mRNA levels of IL-6 and IL-17A in the lymph node were extensively upregulated in GKO hosts It is of interest that anti-IFN-gamma treatment did not improve the allograft survival in IL-17KO hosts Conclusions IFN-gamma and IL-17 play no critical role in the development of minor-specific allograft rejection in C57BL/6 mice This indicates the presence of sophisticated rejection mechanisms that are still elusive and cannot be ascribed simply to Th1, -2, or -17
25 citations
TL;DR: Results demonstrate that IL‐7 is essential for lymphopenia‐driven turnover of colitogenic CD4+ T cells rather than the maintenance of those cells in established colitic mice and provide a basis for the timing of IL‐ 7/IL‐7R blockade for the treatment of inflammatory bowel diseases.
Abstract: We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4(+)CD45RB(high) T cells into IL-7(-/-) x RAG-1(-/-) mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7(-/-) x RAG-1(-/-) mice parabiosed with colitic CD4(+)CD45RB(high) T-cell-transferred RAG-1(-/-) mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4(+) T cells by surgically separating these parabionts. Surprisingly, the separated IL-7(-/-) x RAG-1(-/-) mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7(-/-) x RAG-1(-/-) partners. CD4(+) T cells isolated from the separated RAG-1(-/-) or IL-7(-/-) x RAG-1(-/-) mice were then transferred into new RAG-1(-/-) or IL-7(-/-) x RAG-1(-/-) mice. Regardless of the source of donor cells, RAG-1(-/-) recipients developed colitis, whereas IL-7(-/-) x RAG-1(-/-) recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4(+) T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases.
11 citations