Characterization of T cell precursors in blood

描述(由申请人提供)：T淋巴细胞必须在一生中产生，以维持免疫功能。T细胞是在胸腺中产生的，但胸腺中没有自我更新的干细胞或祖细胞。相反，出生后T细胞的产生依赖于祖细胞的输入，这些祖细胞来自骨髓，并通过血液进入胸腺。虽然骨髓祖细胞似乎能够同时产生T和B系细胞，但最近的数据表明，胸腺内的T细胞前体细胞不具有B系能力。这表明T细胞的指定可以在从骨髓输出之前发生，也可以在进入胸腺时立即发生。了解T细胞命运在哪里被诱导，以及B潜能在哪里丢失，对于理解T细胞重建的近阶段的要求，从而预防或纠正某些T细胞免疫缺陷，包括那些伴随衰老过程的缺陷，甚至与艾滋病毒或其他外部环境攻击相关的潜在缺陷，是至关重要的一步。为了解决长期存在的T谱系分化发生的悖论，我们建议分析具有T谱系能力的血液群体的谱系潜力。血液中T细胞祖细胞的身份也仍然是个谜，所以第一步将是确定血液中哪些群体有能力产生T细胞。随后将确定它们的谱系能力，包括体外使用旨在揭示各种谱系潜力的条件，然后在正常生物条件下的体内。总之，这些方法有望揭示重新填充出生后胸腺的祖细胞的性质，并为进一步研究在哪里寻找指定T细胞谱系承诺和启动T细胞发育的信号提供基础。

DESCRIPTION (provided by applicant): T lymphocytes must be produced throughout life to maintain immune function. T cells are produced in the thymus, but the thymus contains no self-renewing stem cells or progenitors. Rather, post-natal T cell production depends on the input of progenitor cells that derive from the bone marrow, and home to the thymus via the blood. While marrow progenitors appear to be capable of giving rise to both T and B lineage cells, recent data indicate that intrathymic T cell progenitors do not possess B lineage capacity. This suggests that T cell specification could either take place prior to export from the marrow, or immediately upon entry into the thymus. Understanding where T cell fate is induced, and B potential is lost, is an essential step in understanding what the requirements are for the proximal stages of T cell reconstitution, and thus for preventing or correcting certain T cell immunodeficiencies, including those that accompany the aging process, and even potentially those associated with HIV or other external environmental attacks. In order to address the long-standing paradox of where T lineage divergence occurs, we propose to analyze the lineage potentials of blood populations that possess T lineage capacity. The identity of blood-borne T cell progenitors has also remained mysterious, so the first step will be to identify those populations within the blood that have the capacity to give rise to T lineage cells. This will then be followed by determination of their lineage capacity, both in vitro using conditions designed to reveal various lineage potentials, and then in vivo under normal biological conditions. Together these approaches are expected to reveal the nature of progenitor cells that repopulate the post-natal thymus, as well as providing a basis for further studies on where to look for the signals that specify T lineage commitment and initiate T cell development.