Regulation of Progenitor Entry into the Thymus

祖细胞进入胸腺的调节

• 批准号: 7384968
• 负责人: GILBERT J. KERSH
• 金额: $ 19.33万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2008-08-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384968
• 关键词: Abbreviations; Allogenic; Animals; Apoptosis; Blood; Bone Marrow; Bone Marrow Transplantation; Cells; Cellularity; Chimera organism; Clinical; Endothelium; Engraftment; Feedback; Genes; Glycoproteins; Growth; Hematologic Neoplasms; Human; Immune; Immune system; Immunity; Infection; Lead; Ligands; MATK gene; Mediating; Mus; Myeloablative Chemotherapy; Numbers; Opportunistic Infections; Output; Patients; Peripheral; Play; Population; Proto-Oncogene Protein c-kit; Radiation; Regulation; Risk; Role; Selectins; Staging; T-Lymphocyte; Testing; Thymus Gland; Zinc Fingers; cancer therapy; cell type; conditioning; immune function; juvenile animal; novel; novel strategies; progenitor; reconstitution; response; restoration; size; thymocyte; transcription factor; tumor; young adult

DESCRIPTION (provided by applicant): Immune deficiency is becoming a more common clinical problem that will require novel strategies for therapy. This is an issue in the treatment of HIV-infected patients, and in patients that undergo bone marrow transplantation (BMT) to treat hematologic malignancies. In these cases, T cell deficiencies can lead to a high risk of opportunistic infection. Complete reconstitution of immune function requires restoration of the T cell compartment through output of new T cells from the thymus, and robust thymic output of new naive T cells requires rapid attainment of a large thymic cellularity. However, the mechanisms that control thymic cellularity have not been defined. We propose a novel mechanism that controls the size of the thymus in young adult mice. For thymus sizes normally seen in these animals, we hypothesize that the importation of new progenitors into the thymus from the blood is a limiting factor for thymus cellularity, and that there is negative feedback from DN thymocytes to limit importation. This negative feedback sets the homeostatic size of the thymus in young animals. In preliminary studies, we have found that mice deficient in the zinc finger transcription factor early growth response gene 1 (Egr1) have thymuses that are twice as large as thymuses in normal mice. Our studies suggest that Egr1 expression in thymocytes can limit the size of the earliest progenitor population in the thymus. Egr1 does not seem to have an intrinsic effect on progenitors as cells lacking Egr1 can increase the number of both Egr1-deficient and wild type progenitors in mixed radiation BM chimeras. In addition, we have found that p-selectin expression is increased in thymuses that are Egr1-deficient. As expression of p-selectin on the thymic endothelium has been shown to play a role in importation of progenitors into the thymus, we hypothesize that thymocytes provide Egr1- dependent negative feedback to the thymic endothelium to limit the entry of new progenitors into the thymus from the blood. This will be tested by (1) directly determining whether Egr1 expression in CD4/CD8 double negative thymocytes inhibits entry of progenitors into the thymus, and (2) determining if the increases in early thymocyte progenitor number and thymus cellularity that result from Egr1-deficiency are mediated by increased p-selectin expression. Project Narrative: Many patients currently suffer from induced immune system deficiencies that make them subject to a variety of infections. In these cases, new T cells must be generated by the thymus to develop effective immunity. This study explores the regulation of thymus size so that it might be possible to enhance thymus function after induced immune deficiency.

描述（由申请人提供）：免疫缺陷正在成为一个更常见的临床问题，需要新颖的治疗策略。这是治疗艾滋病毒感染患者的问题，以及接受骨髓移植（BMT）以治疗血液系统恶性肿瘤的患者。在这些情况下，T细胞缺陷会导致机会性感染的高风险。免疫功能的完全重建需要通过胸腺的新T细胞输出来恢复T细胞区室，而新的幼稚T细胞的稳健胸腺输出需要快速获得大型胸细胞性。但是，尚未定义控制胸腺细胞性的机制。我们提出了一种新型机制，该机制控制年轻小鼠的胸腺大小。对于通常在这些动物中通常看到的胸腺大小，我们假设从血液中进口新祖细胞是胸腺细胞性的限制因素，并且会产生DN胸腺细胞的负反馈以限制进口的进口。这种负反馈使幼体中胸腺的体内稳态大小。在初步研究中，我们发现缺乏锌指转录因子早期生长反应基因1（EGR1）的小鼠的胸腺是正常小鼠的胸腺的两倍。我们的研究表明，胸腺细胞中的EGR1表达可以限制胸腺最早的祖细胞种群的大小。 EGR1似乎对祖细胞没有内在作用，因为缺乏EGR1的细胞可以增加混合辐射BM嵌合体中EGR1缺陷型和野生型祖细胞的数量。此外，我们发现在Egr1缺陷型的胸腺中，P-选择素表达增加。由于p-选择蛋白在胸腺内皮上的表达已被证明在祖细胞中的进口胸腺中发挥作用，因此我们假设胸腺细胞为胸腺内皮提供了EGR1依赖性负反馈，以限制新祖细胞进入血液中的胸腺。这将通过（1）直接确定CD4/CD8双负胸腺细胞中的EGR1表达抑制祖细胞进入胸腺，以及（2）确定胸腺细胞祖细胞数量的增加和胸腺细胞的增加是否由EGR1缺乏效率引起的EGR1缺乏效率介导了P-塞纤维表达增加。 项目叙述：许多患者目前患有诱发的免疫系统缺陷，使他们受到各种感染。 在这些情况下，胸腺必须生成新的T细胞以发展有效的免疫力。 这项研究探讨了胸腺大小的调节，因此有可能在诱导免疫缺乏后增强胸腺功能。