| Project/Area Number |
17380182
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied veterinary science
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
HATTORI Masakazu KYOTO UNIVERSITY, Graduate School of Biostudies, Associate Professor, 生命科学研究科, 助教授 (40211479)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Yoshimasa KYOTO UNIVERSITY, Graduate School of Biostudies, Assistant Researcher, 生命科学研究科, 助手 (90280700)
NAKAJIMA Yoshiaki KYOTO UNIVERSITY, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (10300724)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2006: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2005: ¥10,700,000 (Direct Cost: ¥10,700,000)
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| Keywords | T-cell immune deficiency / Rap1 / SPA-1 / PD-1 / DNA microarray / Anergy / 免疫不全 / ERK活性化 |
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| Research Abstract |
A Rap1 GTPase-activating protein, SPA-1-deficient mice develop age-dependent T cell unresponsiveness followed by a spectrum of myeloproliferative disorders of late onset. Analysis of T cells in the mice showed the increase of CD4^+ T cells expressing a negative co-receptor, PD-1. Purified PD-1^+CD^4+ T cells in the mice did not respond to anti-CD3 stimulation and did not show ERK phosphorylation while PD-1^-CD4^+ T cells responded to the stimulation. The results indicated that PD-1^+CD4^+ T cells are responsible for T cell unresponsiveness in SPA-1-deficient mice. Combination of PMA with ionophore, however, induced the proliferation of the PD-1^+CD4^+ T cells, indicating that growth machinery of the cells is normal and that growth signal via T-cell receptor (TCR) is blocked between TCR and ERK. PD-1^+CD4^+ T cells remained in existence in normal mice and that they also increased with age. Interestingly, inoculation of BCR-Abl-transformed leukemia cells accelerated the increment of PD-1^+CD4^+ T cells in normal mice. The PD-1^+CD4^+ T cells also exhibited unresponsiveness against TCR stimulation, indicating that inoculation of the leukemia cells induced "anergy" in T cells, which were thought to play important roles in immune surveillance against leukemia cells. To unveil the molecular mechanism(s) on the induction of T cell anergy, we performed DNA microarray analysis between PD-1^+CD4^+ T cells and PD-1^+CD4^+ T cells. The result showed the expression level of IL-1 receptor β-chain (CD121b), OcaB (a transcriptional factor involved in B cell differentiation) and C/EBPα (a transcriptional factor involved in neutrophil differentiation) genes was higher in PD-1^+CD4^+ T cells than in PD-1^-CD4^+ T cells. The results suggest the possibility that these molecules are involved in unresponsiveness of PD-1^+ CD4^+ T cells.
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