The Journal of Experimental Medicine
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Published 16 August 2004. doi:10.1084/jem.20040845
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 4, 411-423
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Bone Marrow Microenvironmental Changes Underlie Reduced RAG-mediated Recombination and B Cell Generation in Aged Mice

Joseph E. Labrie, III1, Alex P. Sah2, David M. Allman2, Michael P. Cancro2, and Rachel M. Gerstein1

1 Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655
2 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Address correspondence to Rachel M. Gerstein, Dept. of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester, MA 01655. Phone: (508) 856-1044; Fax: (508) 856-5920; email: Rachel.Gerstein{at}umassmed.edu

During aging, adaptive immunity is severely compromised, due in part to decreased production of B lymphocytes and loss of immunoglobulin (Ig) diversity. However, the molecular mechanisms that underlie age-associated diminished B cell production remain unclear. Using in vivo labeling, we find that this reduction in marrow pre–B cells reflects increased attrition during passage from the pro–B to pre–B cell pool. Analyses of reciprocal bone marrow chimeras reveal that the magnitude and production rates of pre–B cells are controlled primarily by microenvironmental factors, rather than intrinsic events. To understand changes in pro–B cells that could diminish production of pre–B cells, we evaluated rag2 expression and V(D)J recombinase activity in pro–B cells at the single cell level. The percentage of pro–B cells that express rag2 is reduced in aged mice and is correlated with both a loss of V(D)J recombinase activity in pro–B cells and reduced numbers of pre–B cells. Reciprocal bone marrow chimeras revealed that the aged microenvironment also determines rag2 expression and recombinase activity in pro–B cells. Together, these observations suggest that extrinsic factors in the bone marrow that decline with age are largely responsible for less efficient V(D)J recombination in pro–B cells and diminished progression to the pre–B cell stage.

Key Words: hematopoietic system • antibody formation • B lymphocytes • aging • gene rearrangement

Abbreviation used in this paper: KI, knockin.


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