Elucidating the function of the transcription factor Bhlhe41 during B-1a cell development and in imprinting of B-1a cell self-renewal properties

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B-1a cells are a subset of innate-like B lymphocytes which can contribute to the first line of defense upon pathogen encounter as well as to clearing cellular debris to maintain tissue homeostasis. B-1a cells are primarily generated during fetal and neonatal life and are less efficiently replenished by adult bone marrow, and therefore they maintain their numbers throughout the lifetime of an organism by self-renewal. Although cytokine receptor signaling and certain metabolic requirements are pertinent to B-1a cell self-renewal, the precise molecular mechanisms underlying the ability of B-1a cells to self-renew remain elusive. Moreover, while an instructive role of B cell receptor signaling has been implicated in the diversion toward the B-1a cell lineage, B-1a cell development is still poorly understood. Recently, the transcription factor Bhlhe41 was identified as a key regulator of B-1a cell development and self-renewal. Published results obtained with Bhlhe41 germline-deficient mice suggested that Bhlhe41 plays two temporally distinct roles in B-1a cells – first controlling their development early in ontogeny and later regulating the unique self-renewal properties of mature B-1a cells. However, our preliminary data obtained by conditional deletion of Bhlhe41 during early and late B-1a cell development challenge this model and indicate that Bhlhe41 may be largely dispensable in mature B-1a cells. Moreover, these results also suggest that the unique self-renewal properties of mature B-1a cells are ‘imprinted’ by Bhlhe41 in a narrow time window early in B-1a cell differentiation. Therefore, the ultimate goal of this research project is to elucidate the function of Bhlhe41 during B-1a cell development and in imprinting of B-1a cell self-renewal properties. To accomplish this goal, I will pursue the following specific aims: First, I will thoroughly characterize the B-1a cell compartment upon conditional deletion of Bhlhe41 early and late in B-1a cell development. Second, I will decipher the cellular and molecular function of Bhlhe41 during early B-1a lymphopoiesis, as well as in a system of inducible B-1a cell differentiation recently developed by Prof. Rajewsky’s lab. Finally, as an additional direction, I will also aim to use Bhlhe41 as a molecular marker to identify a so far elusive population of human B 1a cells. Together, the results obtained within this research project will not only be valuable in advancing our understanding of the humoral immune system of mice and men, but also provide significant insights into molecular mechanisms of self-renewal.