Expression of BTB-ZF Transcriptional Regulators as Biomarkers of Immune System Development



 DESCRIPTION (provided by applicant): The BTB/POZ-ZF [Broad complex, Tramtrack, Bric a`brac (BTB) or poxvirus and zinc finger (POZ)-zinc finger] is a protein family of transcriptional regulators. These BTB-zinc finger (BTB-ZF) family members are defined by the presence of an N-terminal protein-protein interaction domain (BTB/POZ) and C-terminal zinc finger domains. Members of this family have emerged as fundamental, non-redundant factors that control the development or function of several different cell types of the immune system. BTB-ZF genes have, for example, been shown to control T cell versus B cell commitment (LRF), CD4 versus CD8 lineage commitment (ThPOK and MAZR), commitment of thymocytes to innate T cell lineages (PLZF), and development of germinal center B cells (Bcl6). Importantly, these genes are not ubiquitously expressed. Indeed, even very closely related cells do not express the same genes. For example, PLZF was found to be expressed in NKT cells, but never in non-innate T cells, B cells, eosinophils, etc. Among γδ T cells, PLZF is only expressed in those with the Vγ1.1Vδ6.3 TCR. ThPOK is expressed in CD4 T cells, but not CD8 T cells. Expression of the BTB-ZF gene family, therefore, is tightly regulated, but when expressed, these genes control fundamental aspects of cell development and/or function. We hypothesize that understanding the expression profile of the BTB-ZF gene family in lymphocytes at the single cell level will offer a profile of the immune system that can be used as a biomarker for immune system function. Each BTB-ZF gene member has the potential to control the function or fate of distinct and specific cellular subsets. Therefore, understanding this gene family will have a profound impact on our understanding of the overall complexity of the immune response. These insights are expected to have important implications for vaccine development, cancer treatment and the management of autoimmune diseases. Working with our neonatology department at RWJMS, we propose to develop high throughput assays to define BTB-ZF expression patterns in discrete populations of lymphocytes at the level of the single cell. Cord blood lymphocytes isolated from full term, Caesarian births will be used for comparison among newborns and for comparison to adult peripheral blood lymphocytes. By this approach, we will define a "baseline" transcription factor profile at birth enabling us to characterize changes that occur in the adult population. We propose that these data, we will enable us to explore quantifiable changes in disease settings. Overall, we anticipate that these data will provide a novel and powerful new means to interrogate the integrity of the human immune system.