| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
1. ICOS is a new member of the CD28 family of costimulatory molecules that is expressed on activated T cells. Its ligand B7RP-1 is constitutively expressed on B cells. Although the blockade of ICOS/B7RP-1 interaction inhibits T cell-dependent Ab production and germinal center formation, the mechanism remains unclear. We speculated that the ICOS/B7RP-1 interaction might be required to up-regulate the expression of a chemokine receptor CXCR5 on CD4 T cells. CXCR5 confers responsiveness to B lymphocyte chemokine (CXCL13). A subset of CD4^+ T cells also express CXCR5, which mediates their migration to the B cell follicles where they provide cognate help to B cells. Thus, CXCR5^+ CD4^+ T cells are referred to as follicular helper T (Th) cells. Previous studies have implicated OX40/OX40 ligand (OX40L) interaction, a pair of the TNFR/TNF family members, in the expression of CXCR5 on CD4^+ T cells. Therefore, we compared the contributions of ICOS/B7RP-1 and OX40/OX40L to the development of CXC
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R5^+ CD4^+ follicular Th cells and GC B cells. Our results indicated that the ICOS/B7RP-1 interaction plays an essential role of follicular Th cells in the spleen and lymph nodes, but the GC formation in lymph nodes is not always dependent on follicular Th cells. On the other hand, a substantial contribution of OX40/OX40L interaction to the development of follicular Th cells and GC B cells was observed only in lymph nodes of certain strains of mice, depending on differential expression of OX40 on follicular Th cells. We also found sub-populations of activated CD4^+ T cells (CXCR5^+ ICOS^+ OX40^- cells, CXCR5^- ICOS^+ OX40^- cells, CXCR5^- ICOS^- OX40^+ cells, and CXCR5^- ICOS^+ OX40^+ cells) in the spleen and LN. It is possible that the three CXCR5^- populations may represent functionally distinct subsets producing Th1 or Th2 cytokines in vivo.
2. We demonstrated that IOCS play a role as costimulatory molecules in NKT cell activation, which augments cytokines production and cytotoxic activity. Less
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