Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice.
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.
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave. N., Worcester 01655, USA.
Joseph E
JE
Labrie
Alex P
AP
Sah
David M
DM
Allman
Michael P
MP
Cancro
Rachel M
RM
Gerstein
D000375:Aging / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology*; D001973:Bromodeoxyuridine; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007111:Immunity, Cellular / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors; D045567:VDJ Recombinases / Q000378:metabolism*
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D045567:VDJ Recombinases; D001973:Bromodeoxyuridine