Astrocytic Inhibition of the Microglial Dendritic Cell Phenotype

外周树突状细胞（DC）是免疫系统的看门狗。当受到刺激时，它们表达DC特异性分子，摄取和加工抗原，并迁移到局部淋巴结，在那里抗原被呈递，从而激活T细胞。然而，小胶质细胞并不是孤立存在的。相反，它们存在于其他细胞类型的海洋中，特别是星形胶质细胞。在初步研究中显示，在星形胶质细胞存在下生长的小胶质细胞抵抗DC特性的假设。因此，与星形胶质细胞一起生长的小胶质细胞不能表达抗原呈递和T细胞活化所必需的分子，其水平与分离培养的小胶质细胞上表达的分子一样高。此外，外周DC的一个突出特征是它们激活T细胞的能力，然而在星形胶质细胞存在下培养的小胶质细胞在执行该功能方面不如它们的分离的对应物有效。这提出了小胶质细胞衍生的DC是不良T细胞活化剂或更间接地促进T细胞分化成调节表型的可能性，其中它们抑制其T细胞同胞的增殖和促炎活化。那么，假设是，虽然小胶质细胞能够表达成熟的DC表型，但它们在很大程度上被星形胶质细胞阻止。此外，该假说进一步提出，在其正常的栖息地，小胶质细胞是耐受性的，从而有助于确保免疫赦免中枢nervous system. To检查这些假说进一步，一个细胞因子鸡尾酒，有效elevening DC特性在孤立的小胶质细胞将被确定。使用这种混合物，将在与星形胶质细胞一起生长的小胶质细胞中引发的DC标志物与从它们分离生长的那些进行比较。T细胞暴露于与或不与星形胶质细胞培养的小胶质细胞的特性将检查与调节T细胞特性的发展特别强调。最后，将检查几种候选物作为DC表型的可能的可溶性星形胶质细胞衍生的抑制剂。这些包括TGF-家族成员、前列腺素家族成员和白细胞介素-10。抑制这些分子将有助于确定它们是否抑制成熟DC表型的表达。更广泛的影响：Jonakait和Ganea博士多年来一直参与研究生和本科生的培训。Jonakait博士是新泽西理工学院的教员，该学院与新泽西州纽瓦克的罗格斯大学共用一个生物系。据《美国新闻世界报道》报道，这些机构拥有全国最多样化的两个学生团体。2005年春天，Jonakait博士和Ganea教授了一门新开设的神经免疫学研究生课程。这将在2007年重演。 这两个学院都有一个证明和持续的承诺，以扩大科学劳动力。 少数民族的成员为实验室做出了重要贡献，本科生在最负盛名的专业和研究生课程中继续深造。最后，Jonakait博士和Ganea博士都是FASEB神经免疫学会议的前任主席，Jonakait博士是首届神经元/神经胶质相互作用戈登会议的前任联合主席（2003年2月），部分由NSF赞助。

Peripheral dendritic cells (DCs) are watchdogs of the immune system. Upon stimulation they express DC-specific molecules, take up and process antigen, and migrate to local lymph nodes where that antigen is presented, thereby activating T cells.Resident brain microglia are the immunological watchdogs of the central nervous system and are capable of expressing similar DC-like properties when isolated and stimulated in vitro. However, microglia do not exist in isolation. Rather, they reside in a sea of other cell types, notably astrocytes. In Preliminary Studies it was shown that microglia grown in the presence of astrocytes resist the assumption of DC properties. Thus, microglia grown with astrocytes fail to express molecules necessary for antigen presentation and T cell activation at levels as high as those expressed on microglia that are cultured in isolation. Moreover, a prominent feature of peripheral DCs is their ability to activate T cells, yet microglia cultured in the presence of astrocytes are less efficient than their isolated counterparts in performing this function. This raises the possibility that microglial-derived DCs either are poor T cell activators or, more provocatively, promote the differentiation of T cells into a regulatory phenotype, in which they suppress the proliferation and proinflammatory activation of their T cell compatriots. The hypothesis, then, is that while microglia are capable of expressing a mature DC phenotype, they are largely prevented from doing so by astrocytes. Moreover, the hypothesis goes further in proposing that in their normal habitat, microglia are tolerogenic, thus helping to ensure immune privilege within the central nervous system.In order to examine these hypotheses further, a cytokine cocktail that efficiently elicits DC properties in isolated microglia will be determined. Using this cocktail, DC markers elicited in microglia grown with astrocytes will be compared to those grown isolated from them. Properties of T cells exposed to microglia cultured with or without astrocytes will be examined with a particular emphasis on the development of regulatory T cell properties. Finally, several candidates will be examined as possible soluble astrocyte-derived inhibitors of the DC phenotype. These include members of the TGF-family, members of the prostaglandin family, and interleukin-10. Inhibition of these molecules will help to determine whether they dampen the expression of a mature DC phenotype.BROADER IMPACT: Drs. Jonakait and Ganea have been involved with training graduate students and undergraduates for many years. Dr. Jonakait is on the faculty at New Jersey Institute of Technology, which shares a biology department with Rutgers University in Newark, NJ. According to U.S. News & World Report, these institutions have two of the most diverse student bodies in the country. In the spring of 2005, Drs Jonakait and Ganea taught a newly-created graduate course in Neuroimmunology. This will be repeated in 2007. Both faculty have a demonstrated and continuing commitment to broadening the scientific workforce. Members of underrepresented minorities have made important contributions to both labs and undergraduate students have gone on to further study at the most prestigious professional and graduate programs.Finally, Drs. Jonakait and Ganea are both past chairs of the FASEB conference on Neuroimmunology, and Dr. Jonakait is the past co-chair of the inaugural Gordon conference on Neuronal/Glial Interactions (February 2003), sponsored in part by NSF.