| Project/Area Number |
16590412
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
YAGI Junji Tokyo Women's Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (70182300)
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| Co-Investigator(Kenkyū-buntansha) |
UCHIYAMA Takehiko Tokyo Women's Medical University, School of Medicine, Professor, 医学部, 教授 (00050550)
IMANISHI Kenichi Tokyo Women's Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (20132920)
ARIMURA Yutaka Tokyo Women's Medical University, School of Medicine, Research Associate, 医学部, 助手 (10281677)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | costimulatory signal / receptor for costimulatory signal / ICOS / STATS / helper T cell differentiation / IL-2 / IL-4 / Co-stimulation / Th cell differentiation / LAT |
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| Research Abstract |
During 2004, we examined an intracellular signaling in T cells triggered by ICOS, and found that various signaling events were induced by ICOS engagement in the absence of anti-CD3 antibodies whereas anti-CD28 antibodies alone did not elicit any signaling events. Further results indicated that the stimulation of T cells with anti-ICOS antibodies alone induced the phosphorylation of tyrosine residues in a 〜38 kDa molecule. This molecule was found to be an adaptor molecule, LAT, from the results of immunoprecipitation, and the level of phosphorylated tyrosine was increased in the presence of anti-CD3 antibodies. In sucrose gradient fractionation, both ICOS and CD28 were located out of membrane lipid raft. The distance and the position from membrane lipid raft were not different between ICOS, CD28 and LAT molecules. Thus, these results suggest that ICOS exerts multiple functions by triggering a diverse signaling via LAT.
During 2005, to clarify an immunoregulatory pathway linking IL-4 to ICOS in Th2 differentiation, which is triggered by IL-2, we examine the difference in this pathway between BALB/c and C57BL/6. The results showed IL-4, the production of which is induced by IL-2, to be much more abundantly produced by BALB/c naive CD4^+ T cells than by C57BL/6 naive CD4^+ T cells. STAT5 was preferentially activated by IL-2 and IL-4 in CD4^+ T cells developing in BALB/c in contrast to the corresponding cells in C57BL/6. STAT5A^<-/-> naive CD4^+ T cells with the BALB/c genetic background showed markedly less IL-4 production than BALB/c cells. Conversely, forced expression of the constitutively active forms of STAT5A and STAT5B in C57BL/6 naive CD4^+ T cells promoted the differentiation of Th2 cells. Thus, these results indicate IL-4 production by naive CD4^+ T cells, in which STAT5 activation is involved and directly controlled by the genetic background, to influence Th cell differentiation in murine strains.
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