Astrocytic Inhibition of the Microglial Dendritic Cell Phenotype

New Jersey Institute Of Technology, Newark NJ

Investigators

Abstract

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.