Reduction of early B lymphocyte precursors in transgenic mice overexpressing the murine heat-stable antigen.
To study the role of the murine heat-stable Ag (HSA) in lymphocyte maturation, we generated transgenic mice in which the HSA cDNA was under the transcriptional control of the TCR V beta promoter and Ig mu enhancer. The HSA transgene was expressed during all stages of B lymphocyte maturation. Expression was first detected in the earliest lymphoid-committed progenitors, which normally do not express HSA, and subsequently reached the highest levels in pro- and pre-B cells. In bone marrow, the number of IL-7-responsive clonogenic progenitors was < 4% of normal, whereas the frequency of earlier B lymphocyte-restricted precursors, detectable as Whitlock-Witte culture-initiating cells, was normal. Pro- and pre-B cells detected by flow cytometry were reduced by approximately 50% relative to controls. Mature splenic B cells were also reduced but to a lesser extent than in marrow, and their response to LPS stimulation was impaired. Reconstitution of SCID and BALB/c-nu/nu mice with HSA transgenic marrow indicated that the perturbations in B lymphopoiesis were not caused by a defective marrow microenvironment or by abnormal T cells. Our previous studies showed elevated HSA expression throughout thymocyte development, which resulted in a profound depletion of CD4+CD8+ double-positive and single-positive thymocytes. Together, these results indicate that HSA levels can determine the capacity of early T and B lymphoid progenitors to proliferate and survive. Therefore, HSA could serve as an important regulator during the early stages of B and T lymphopoiesis.
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
M R
MR
Hough
M S
MS
Chappel
G
G
Sauvageau
F
F
Takei
R
R
Kay
R K
RK
Humphries
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology*; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D051927:CD24 Antigen; D002454:Cell Differentiation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D015851:Interleukin-7 / Q000494:pharmacology; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011828:Radiation Chimera; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000235:genetics; D013154:Spleen / Q000166:cytology; D019076:Transgenes
D015703:Antigens, CD; D051927:CD24 Antigen; C497890:Cd24a protein, mouse; D007148:Immunoglobulin mu-Chains; D015851:Interleukin-7; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins