NK cells in the CD19- B220+ bone marrow fraction are increased in senescence and reduce E2A and surrogate light chain proteins in B cell precursors.
E2A encoded proteins, key transcriptional regulators in B lineage specification and commitment, have been shown to decrease in B cell precursors in old age. E2A regulates genes encoding the surrogate light chain proteins lambda5 and VpreB. In old age, B cell precursors express less surrogate light chain and this results in compromised pre-B cell receptor function and diminished expansion of new pre-B cells in senescence. Herein, we show that aged bone marrow has increased Hardy Fraction A (CD19(-) B220(+)) cells, including NK cells, that can inhibit both E47 (E2A) protein and surrogate light chain protein expression in B cell precursors. In vitro, NK-associated inhibition of E47 protein is contact-independent and partially reversed by neutralization of TNFalpha. In vivo, depletion of NK cells in aged mice by treatment with anti-asialo GM1 antibody led to restoration of surrogate light chain protein levels to that typical of young B cell precursors. These studies suggest that NK cells, within the CD19(-) B220(+) bone marrow cell fraction, may contribute to a bone marrow microenvironment that has the potential to negatively regulate E47 (E2A) as well as surrogate light chain levels in B cell precursors in old age.
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Anne M
AM
King
Patricia
P
Keating
Anjali
A
Prabhu
Bonnie B
BB
Blomberg
Richard L
RL
Riley
D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000276:immunology*; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D015536:Down-Regulation; D005677:G(M1) Ganglioside / Q000378:metabolism; D054444:Immunoglobulin Light Chains, Surrogate / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000032:analysis*; D038041:Lymphopoiesis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology; D051820:TCF Transcription Factors / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018941:Antigens, CD19; D051792:Basic Helix-Loop-Helix Proteins; D005677:G(M1) Ganglioside; D054444:Immunoglobulin Light Chains, Surrogate; D017493:Leukocyte Common Antigens; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014409:Tumor Necrosis Factor-alpha; C075668:Tcf3 protein, mouse; C544913:Tcf7l1 protein, mouse; C018835:asialo GM1 ganglioside