The goal of this proposal is to characterize early B cell precursors and to investigate the regulation of primary B cell differentiation by bone marrow stromal cells.
The first aim will assess the proliferative and differentiative potential of cells that express the early B cell marker, BP-1/6C3, by measuring their potential to reconstitute and maintain B cells following their injection into SCID mice. This study will elucidate if these cells can maintain steady state B lymphopoiesis or if input from a more immature cell compartment is necessary.
The second aim i s to further characterize defined stromal cell derived factors and identify additional mediators with effects on B lymphopoiesis. Specific experiments will examine if early B cell precursors that have not yet expressed the B220 antigen are IL-7 responsive, determine if IL-7 is involved in the maturation of pre-B cells into B lymphocytes, and explore potential synergistic/additive effects of IL-7 with other cytokines. Finally, a cDNA library prepared from the S17 stromal cell line will be screened using expression vector strategies in order to identify a non-IL-7 factor from the S17 stromal cell line that potentiates the formation of clonal, pre-B cell colonies in semi-solid medium. The cells in these colonies express cytoplasmic u heavy chain protein but not kappa. The objective of the third aim is to determine the status of light chain gene rearrangements of cells in S17 supported colonies in order to define the precise molecular stage at which the S17 factor acts. An inverted PCR approach will be used for this analysis. Cytokines play a key role in B lymphopoiesis, but contact between developing B cells and stromal cells also occurs.
The fourth aim will use anti-stromal cell monoclonal antibodies to identify and biochemically characterize cell surface determinants important in stromal cell-lymphocyte interactions. Taken together, the data from these studies will further elucidate a fundamental developmental process and be of value in understanding abnormalities of B lymphopoiesis.
|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|
|Sham, Caroline W; Chan, Ann M; Kwong, Jacky M K et al. (2012) Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice. J Neuroophthalmol 32:227-37|
|Montecino-Rodriguez, Encarnacion; Dorshkind, Kenneth (2012) B-1 B cell development in the fetus and adult. Immunity 36:13-21|
|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|
|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|
|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|
|Chen, Ling; Sham, Caroline W; Chan, Ann M et al. (2009) Role of the immune modulator programmed cell death-1 during development and apoptosis of mouse retinal ganglion cells. Invest Ophthalmol Vis Sci 50:4941-8|
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