| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1998: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Research Abstract |
Two classes of T cells, namely, T cells expressing T-cell receptor-αβ(TCR-αβ) and T cells expressing TCR-γδ, have been identified in all vertebrates examined to date. It is now clear that most αβ T cells recognize peptide fragments of antigens presented by major histocompatibility complex molecules and are engaged in most characterized cell-mediated antigen-specific immune responses. In contrast, the general rules forγδT-cell recognition remain undefined and the biologic roe ofγδT cells in immune responses is not well understood.
We analyzed the cytolytic activity of intraepithelial T cells (IEL) isolated from the small intestines of 2- to 3-month-old mutant mice rendered deficient in different gene(s) in which the number of IEL expressing either TCR-αβ(αβ-IEL) or TCR-γδ(γδ-IEL) were absent or markedly diminished. When compared with wild-type (WT) littermates, cytolytic activity ofγδ-IEL was sharply attenuated in TCR-β mutant (βィイD1-/-ィエD1) mice but remained unaltered in TCR-α mutant (α
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ィイD1-/-ィエD1) mice. The anti-CD3 and anti-TCR-γδ mAb-induced IFN-γ production of γδ-IEL showed the same TCR-α and TCR-β mutation-dependent variability.
In contrast to βィイD1-/-ィエD1 mice, αィイD1-/-ィエD1 mice are predisposed to a marked increase in antibody producing B cells secreting autoantibodies and to germinal center formation. In fact, the traits are comparable to or even exceed those of age-matched wt mice and the cellular mass of lymphoid tissues in αィイD1-/-ィエD1 mice becomes greater than that in control wt mice, either after exposure to environmental antigens or with age. Our present study revealed that, even during 2-3 months of young adult age, cytolytic and IFN-γ-producing activities of γδ-IEL were uniformly high in αィイD1-/-ィエD1 mice but very low in βィイD1-/-ィエD1 mice. Analysis of large intestinal γδ-IEL from 2- to 3-month-old αィイD1-/-ィエD1 and βィイD1-/-ィエD1 mice indicated that they were also cytolytic in the former but not in the latter mutant mice, In this context, the persistent colonization of constitutively activated Thy-1ィイD1+ィエD1 γδ-IEL subset in the intestinal epithelia of young αィイD1-/-ィエD1 mice probably has important implications for the subsequent development of inflammatory bowel disease (IBD) in older αィイD1-/-ィエD1 mice. Thus, not only the βィイD1dimィエD1 T cells, but also possibly the activated γδ T cells in the intestinal mucosa, may play an important role in the early stages of development of chronic IBD in αィイD1-/-ィエD1 mice. Less
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