ABSTRACT
Senescent mice exhibit decreased numbers of pre-B cells in the bone marrow. Herein, we show that the molecules, lambda5 and VpreB, which comprise the surrogate light chain component of the pre-B cell receptor, are reduced in pro-B/early pre-B cells derived in vitro from the bone marrow of 18-27 months old BALB/c mice after stimulation with IL-7. Both lambda5 and VpreB expression were decreased at the mRNA level as indicated by semi-quantitative RT-PCR; this suggests that the reduced surrogate light chains seen in senescent B cell precursors result from dysfunctional transcriptional regulation. The transcription of surrogate light chains is regulated, in part, by E2A (E47) gene products. Levels of E2A proteins, including E47, were decreased in senescent B cell precursors by up to 90%. Reduced E2A (E47) expression and subsequent reduced transcription of the surrogate light chain components lambda5 and VpreB may, in part, explain the diminished production of B lineage cells observed in senescence.
Subject(s)
Aging/immunology , Aging/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , DNA-Binding Proteins/metabolism , Hematopoietic Stem Cells/immunology , Hematopoietic Stem Cells/metabolism , Immunoglobulin Light Chains/metabolism , Membrane Glycoproteins/metabolism , Transcription Factors , Aging/genetics , Animals , B-Lymphocytes/cytology , DNA-Binding Proteins/genetics , Female , Hematopoiesis , Hematopoietic Stem Cells/cytology , Immunoglobulin Light Chains/genetics , Immunoglobulin Light Chains, Surrogate , In Vitro Techniques , Male , Membrane Glycoproteins/genetics , Mice , Mice, Inbred BALB C , RNA, Messenger/genetics , RNA, Messenger/metabolism , TCF Transcription Factors , Transcription Factor 7-Like 1 ProteinABSTRACT
Although senescent BALB/c mice (approximately 2 years old) have reduced numbers of small pre-B cells, early pre-B cells (CD43+CD25+B220+) are present in comparable numbers within the bone marrow of both young (3-6-month-old) and senescent BALB/c mice. The transition of CD43+ pre-B cells to the CD43- pre-B cell compartments is dependent on proliferation and clonal maturation dictated by the pre-B cell receptor (mu/lambda5/VpreB). In vivo, senescent CD43+B220+ pro-B/early pre-B cells demonstrated reduction of lambda5 mRNA, by RT-PCR analysis, and of both surface and cytoplasmic lambda5 protein. Decreased lambda5 protein expression was also seen among pro-B/pre-B cells derived from senescent bone marrow after stimulation in vitro with IL-7. We propose that diminished expression of the lambda5 surrogate light chain results in decreased pre-B cell receptor formation and contributes to reduced recruitment of nascent CD43+ pre-B cells into the CD43- large and small pre-B cell compartments.
