IMMUNOREGULATORY CIRCUITS IN MAN

在功能和表型方面已经取得了很大进展。 基于表达的CD4群体内存在的异质性 不同的细胞表面结构，如CD45和CD29/VLA 抗原和这些细胞表面结构在T细胞活化中的作用 和功能。VLA/CD29抗原优先表达于 CD45RO+CD45RA--“记忆”(辅助者/诱导者)子集以及CD29/VLA 整合素可以作为多种细胞类型的信号受体。 包括T淋巴细胞。这其中涉及的机制的细节 信号转导和随后对T细胞功能的影响还远不清楚。 尽管有报道称许多表面分子优先表达 在CD45RA-CD45RO+记忆性T细胞上，许多研究已经集中在功能和功能上。 这些细胞的激活机制，对细胞表面知之甚少 CD45RA+CD45RO优先表达的分子--“幼稚” (抑制子/诱导子)细胞或关于这个的实际功能程序 除抑制子诱导功能外的细胞亚群。这一行动的主要目标是 建议确定监管电路的结构基础 参与CD4细胞亚群的正、负性免疫调节。 这项建议的具体目标是：1)结构基础 CD29/VLA介导的信号转导及其在T细胞活化和功能中的作用 在T细胞中，哪些VLA-α链参与pp105酪氨酸磷酸化 细胞和pp105的分子结构将被研究。此外， Pp105和CD29VLA介导的信号在不同亚群中的生物学意义 T细胞将被确定。2)CD27在功能程序中的作用 CD45RA+T细胞。将建立CD45RA+CD27+克隆并发挥其作用 将对CD27在这些克隆中的调控功能进行研究。此外， CD27参与T细胞活化的生化途径及其机制 利用基因转移方法在T细胞中发挥CD27的功能将是 下定决心。此外，还将制备可溶性CD27分子，并 可溶性CD27对T细胞功能和活化的生物学效应 以及CD27的假定配体将被确定。3)新的 CD45RA+T细胞表面分子的单抗探针 以及它们在这些细胞的功能和激活中的作用 将对细胞进行研究。4)患者的分子和细胞缺陷 患有自身免疫性疾病。慢性阻塞性肺疾病患者T细胞精确表型分析 患有自身免疫性疾病的患者。利用新的单抗 (在AIM 3中开发的CD27、CD31和单抗)将被执行。此外， VLA/CD29在慢性粒细胞白血病患者T细胞活化和功能中的作用 自身免疫性疾病与CD27介导的信号和可溶性CD27的作用 来自自身免疫性疾病患者的T细胞将被确定。我们的 这些项目不仅将为T细胞的分子机制提供新的数据 细胞活化和T细胞免疫调节，但也将提供新的 对自身免疫病理生理机制的认识 系统性红斑狼疮和干燥综合征等疾病。

Much progress has been made regarding the functional and phenotypic heterogeneity that exists within the CD4 population based on the expression of different cell surface structures such as CD45 as well as CD29/VLA antigens and the role of these cell surface structures in T cell activation and function. The VLA/CD29 antigens preferentially expressed on the CD45RO+CD45RA- "memory" (helper/inducer) subset and furthermore CD29/VLA integrins can act as signalling receptors in a variety of cell types including T lymphocytes. The details of mechanisms involved in this signalling and subsequent effects upon T cell function are far from clear. Although many surface molecules are reported to be preferentially expressed on CD45RA-CD45RO+ memory T cells and many have focused on the function and activation mechanisms of these cells, little is known about cell surface molecules preferentially expressed on CD45RA+CD45RO-"naive" (suppressor/inducer) cells or about the actual functional programs of this cell subset except for suppressor inducer function. The major goal of this proposal is to determine the structural basis of the regulatory circuits involved in positive and negative immunoregulation by CD4 cell subsets. The specific aims of this proposal are: 1) The structural basis of CD29/VLA-mediated signaling an its role in T cell activation and function. Which VLA-alpha chains are involved in pp105 tyrosine phosphorylation in T cells and the molecular structure of pp105 will be studied. Moreover, biological significance of pp105 nd CD29VLA-mediated signals in subsets of T cells will be determined. 2) The role of CD27 in the functional programs of CD45RA+ T cells. CD45RA+CD27+clones will be established and the role of CD27 in the regulatory function of these clones will be studied. Moreover, the biochemical pathways of CD27 involved in T cell activation and the function of CD27 in T cells utilizing gene transfer methods will be determined. In addition, soluble CD27 molecule will be prepared and the biological effects of soluble CD27 on T cell function and activation as well as the putative ligand for CD27 will be determined. 3) New monoclonal antibody probes to cell surface molecules on CD45RA+ T cells will be developed and their role in the function and activation of these cells will be studied. 4) The molecular and cellular defects in patients with autoimmune diseases. Analysis of the precise T cell phenotypes in patients with autoimmune diseases. Utilizing new monoclonal antibodies (CD27, CD31 and Mabs developed in Aim 3) will be performed. Moreover, the role of VLA/CD29 in activation and function of T cells from patients with autoimmune diseases and the CD27 mediated signals and role of soluble CD27 in T cells from patients with autoimmune diseases will be determined. Our projects would not only provide new data for the molecular mechanisms of T cell activation and T cell immune regulation but will also provide new insights into understanding the pathophysiologic mechanisms of autoimmune diseases such as SLE and Sjogren's syndrome.