| Budget Amount *help |
¥16,830,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2007: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2006: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Research Abstract |
T lymphocytes are the cells that play an essential role in distinguishing non-self from self. T lymphocytes acquire this ability through shaping a repertoire of recognition specificity during the development in the thymus, by the process referred to as positive and negative selection. Much has been revealed regarding how antigen-receptor signals in developing T lymphocytes control cell fate upon positive and negative selection. However, how T lymphocytes are generated and selected in the thymus environment is still poorly understood. The present study showed that mice doubly deficient for chemokine receptors CCR7 and CCR9 were defective specifically in fetal thymus colonization before, but not after, thymus vascularization. The defective prevascular fetal thymus colonization was followed by selective loss of the first wave of T-cell development generating epidermal Vγ3(+) γδ T cells. Unexpectedly, CCL21, a CCR7 ligand, was expressed not by Foxn1 -dependent thymic primordium but by Gcm2
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-dependent parathyroid primordium, whereas CCL25, a CCR9 ligand, was predominantly expressed by Foxn1 -dependent thymic primordium, revealing the role of the adjacent parathyroid in guiding fetal thymus colonization. These results indicate coordination between Gcm2-dependent parathyroid and Foxn1 -dependent thymic primordia in establishing CCL21/CCR7- and CCL25/CCR9-mediated chemokine guidance essential for prevascular fetal thymus colonization. This study also showed the noninvasive detection of thymocytes in transgenic medaka that express fluorescent protein under the control of immature-lymphocyte-specific ragl. We showed that lymphoid progenitor cells colonized the thymus primordium in an anterior-to-posterior orientation-specific and multiple-chemokine-dependent manner, revealing that extrathymic anterior chemotactic components guide prevascular thymus colonization. We also show that developing thymocytes acquire the random walk motility along with the expression of antigen receptors and coreceptors, suggesting that thymocyte walking is initiated at the developmental stage for repertoire selection. Thus, this study for the first time enabled real-time intravital imaging of thymocytes without surgical invasion. Less
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