Characterization of a B-1 cell transcriptional regulator

Myriads of cell types exist in complex organisms such as mice and humans. Each cell type has its own unique set of functions. Execution of a molecular program that allows fulfillment of these functions is guided by a set of molecular regulators unique for each cell type. Identification and characterization of such regulators is instrumental for our understanding of the biology of a given cell. B-1 cells are a subset of B lymphocytes that serve as the first line of defense against pathogens. A number of properties, such as their location in the body, ability to self-renew throughout the lifetime of an organism, and spontaneous secretion of antibodies, distinguish them from the other B lymphocytes. Surprisingly little is known about regulators that orchestrate these unique properties of B-1 cells. In our preliminary studies we identified such a regulator. In its absence, B-1 cells were severely reduced in numbers and showed abnormal properties. In this proposal, we suggest experiments that will allow us to understand the exact function of this regulator at the cellular and molecular level. These experiments will allow us to demonstrate, whether it is required for the survival, proliferation or differentiation of B-1 cells, as well as to define the molecular program that it orchestrates.

In this study we identified a novel regulator of cells responsible for the first line of antibody-mediated immune responses to pathogens. Myriads of cell types exist in complex organisms such as mice and humans. Each cell type has its own unique set of functions. Execution of a molecular program that allows fulfillment of these functions is guided by a set of molecular regulators unique for each cell type. Identification and characterization of such regulators is instrumental for our understanding of the biology of a given cell. B-1 cells are a subset of B lymphocytes that serve as the first line of defense against pathogens. A number of properties, such as their location in the body, ability to self- renew throughout the lifetime of an organism, and spontaneous secretion of antibodies, distinguish them from the other B lymphocytes. Surprisingly little is known about regulators that orchestrate these unique properties of B-1 cells. In our preliminary studies we identified one of the first regulators of B-1 cells transcription factor Bhlhe41. In the course of this project we revealed cellular and molecular mechanisms by which this protein regulates B-1 lymphocytes. Our work demonstrated that in the absence of Bhlhe41 B-1 cells are drastically decreased in numbers that is explained both by a defect in their development and by loss of their ability to self-renew. Moreover, the remaining cells also had altered repertoire of antibodies. On the molecular level that was at least in part explained by the function of Bhlhe41 in dampening activity of the genes involved in proliferation, negative regulation of B cell receptor signaling, as well as activation of genes involved in B-1 cell survival. This work also paved the way to the investigation of broader functions of Bhlhe41 and its close relative, Bhlhe40, in the immune system including their function in other self-renewing populations, such as tissue-resident macrophages, and in regulation of antibody-mediated immune responses.