Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice

J Exp Med. 2004 Aug 16;200(4):411-23. doi: 10.1084/jem.20040845.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / immunology*
  • Animals
  • B-Lymphocytes / immunology*
  • Bone Marrow / immunology*
  • Bromodeoxyuridine
  • DNA-Binding Proteins / metabolism*
  • Flow Cytometry
  • Gene Expression Regulation
  • Immunity, Cellular / immunology*
  • Mice
  • Mice, Inbred Strains
  • Time Factors
  • VDJ Recombinases / metabolism*

Substances

  • DNA-Binding Proteins
  • Rag2 protein, mouse
  • V(D)J recombination activating protein 2
  • VDJ Recombinases
  • Bromodeoxyuridine