Numerous studies have revealed differences in the transcriptional regulation of B lymphopoiesis in the embryo and the adult. In addition, B lineage cells isolated from fetal liver and adult bone marrow exhibit differential sensitivity to selected cytokines. The central hypothesis of this proposal is that these differences exist because B-1 progenitors and their progeny are the dominant B lineage cells present in the embryo and that the intra- and extra-cellular signals to which they respond are distinct from those that regulate the development of B-2 B cells. This premise is based on recent studies from our laboratory demonstrating that B-1 B cell progenitors, identified by their unusual Lin- CD45Rlow/- CD19+ phenotype, are the major B cell progenitor population present in the fetus. The goals of this proposal are to determine when and where in the embryo B-1 progenitors emerge and test the hypothesis that the regulatory controls operative on them are distinct from those in the B-2 lineage.
Aim 1 will take advantage of recent advancements in the phenotypic resolution of B-1 and B-2 progenitors to define when and in which embryonic tissues B-1 and B-2 B specified progenitors appear and expand and test the hypothesis that B-1 B cells are part of the primitive wave of hematopoiesis. Experiments in Aim 2 will use loss and gain of function approaches in order to identify transcription factors whose expression is required for B-1 development and test the hypothesis that the transcriptional regulation of B-1 and B-2 development is distinct. Fetal and adult B lineage cells exhibit distinct responses to various microenvironmental and systemic signals, and we propose that these differences are due to the differential effects of these stimuli on B-1 and B-2 progenitors. Testing this possibility is the goal of Aim 3. Taken together, the results form this study will provide a comprehensive picture of fetal B cell development that is of relevance to the fields of immunodeficiency, leukemogenesis, and hematopoietic stem cell transplantation.

Public Health Relevance

B cell development initiates during embryogenesis, but little is known about this process. The results obtained from the experiments in this application will provide a comprehensive understanding of fetal B lymphopoiesis that will be of relevance to the fields of immunodeficiency, autoimmunity, leukemogenesis, and hematopoietic stem cell transplantation.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Nasseri, M Faraz
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Montecino-Rodriguez, Encarnacion; Casero, David; Fice, Michael et al. (2018) Differential Expression of PU.1 and Key T Lineage Transcription Factors Distinguishes Fetal and Adult T Cell Development. J Immunol 200:2046-2056
Montecino-Rodriguez, Encarnacion; Fice, Michael; Casero, David et al. (2016) Distinct Genetic Networks Orchestrate the Emergence of Specific Waves of Fetal and Adult B-1 and B-2 Development. Immunity 45:527-539
Montecino-Rodriguez, Encarnacion; Li, Katy; Fice, Michael et al. (2014) Murine B-1 B cell progenitors initiate B-acute lymphoblastic leukemia with features of high-risk disease. J Immunol 192:5171-8
Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2012) B-1 B cell development in the fetus and adult. Immunity 36:13-21
Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2011) Formation of B-1 B cells from neonatal B-1 transitional cells exhibits NF-?B redundancy. J Immunol 187:5712-9
Yoshimoto, Momoko; Montecino-Rodriguez, Encarnacion; Ferkowicz, Michael J et al. (2011) Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proc Natl Acad Sci U S A 108:1468-73
Barber, Chad L; Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2011) Reduced production of B-1-specified common lymphoid progenitors results in diminished potential of adult marrow to generate B-1 cells. Proc Natl Acad Sci U S A 108:13700-4
Signer, Robert A J; Montecino-Rodriguez, Encarnacion; Witte, Owen N et al. (2010) Immature B-cell progenitors survive oncogenic stress and efficiently initiate Ph+ B-acute lymphoblastic leukemia. Blood 116:2522-30