Murine pro-B cells require IL-7 and its receptor complex to up-regulate IL-7R alpha, terminal deoxynucleotidyltransferase, and c mu expression.
Phenotypic analysis of bone marrow cells from IL-7 knockout (KO) mice revealed that B cell development is blocked precisely at the transition between pro-B cells and pre-B cells. In contrast, the generation of pre-pro-B cells and pro-B cells appeared to be normal, as judged by total cell numbers, proliferative indexes, D-JH and V-DJH gene rearrangements, and mRNA for recombinase-activating gene-1 (RAG-1), RAG-2, TdT, Ig mu, lambda 5, and VpreB. However, upon closer inspection, several abnormalities in pro-B cell development were identified that could be corrected by injection of rIL-7 in vivo. These included the absence of the subset of late pro-B cells that initiates cmu expression for pre-B cell Ag receptor (BCR) formation, and the failure of pro-B cells to up-regulate TdT and the IL-7R alpha (but not the common gamma-chain) chain. Similar defects were present in common gamma-chain and Jak3 KO mice, but not in lambda 5 or (excluding cytoplasmic Ig mu heavy chain (c mu)) RAG-1 KO mice, all of which also arrest at the late pro-B cell stage. Consequently, up-regulation of TdT and IL-7R alpha expression requires signaling through the high affinity IL-7R, but does not require cmu expression or a functional pre-BCR. Taken together, these results suggest that IL-7 and its receptor complex are essential for 1) up-regulating the expression of TdT and IL-7R alpha, 2) initiating the production of cmu and 3) promoting the formation of a functional pre-BCR in/on pro-B cells. These key events, in turn, appear to be prerequisite both for differentiation of pro-B cells to pre-B cells and for proliferation of these cell subsets upon continued stimulation with IL-7.
Wei
C
C
Department of Pathology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Zeff
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R
Goldschneider
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D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D004253:DNA Nucleotidylexotransferase / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D018398:Homeodomain Proteins / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000096:biosynthesis / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis* / Q000235:genetics; D015851:Interleukin-7 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053616:Janus Kinase 3; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis*; D013234:Stem Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology*
D018398:Homeodomain Proteins; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains; D007148:Immunoglobulin mu-Chains; D015851:Interleukin-7; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; C064658:RAG-1 protein; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D004253:DNA Nucleotidylexotransferase