Bone marrow declines as a site of B-cell precursor differentiation with age: relationship to thymus involution.
The rearrangement of immunoglobulin genes in B-lymphocyte precursors requires the expression of the recombination activating genes (Rag), which leads to the generation of a highly diverse B-cell repertoire. We can use the level of Rag-1 mRNA in the bone marrow as an index of its capacity to support the maturation of B lymphocytes as all detectable bone marrow Rag-1 mRNA is expressed by B-cell precursors. In mouse bone marrow, Rag-1 mRNA increases during the first 2 months of life to reach its maximal level at 2 months of age. This level is maintained until 5 months of age and thereafter declines to a minimum level by 10 months of age. Thus, bone marrow Rag-1 mRNA is highest at the time when thymic function is maximal in euthymic mice. An association between thymic activity and bone marrow Rag-1 gene expression was supported by showing a low level of bone marrow Rag-1 mRNA in athymic nude mice at an age when this gene is maximally expressed in euthymic mice. Another characteristic of B cells in nude mice is their preferential rearrangement of diversity region (D)-proximal heavy-chain variable region (VH) genes. We demonstrated that injection of syngeneic splenic T cells into nude mice not only stimulates an increase in Rag-1 mRNA in their bone marrow B-cell precursors but also restores their random use of VH genes. Most interestingly, injection of supernatant medium from phytohemagglutinin-activated splenic T-cell cultures from young euthymic mice also induces both Rag-1 mRNA in bone marrow B-cell precursors and random use of VH genes. These findings suggest that thymic function can regulate both Rag-1 gene expression and VH gene use by bone marrow B-cell precursors.
Ben-Yehuda
A
A
Division of Geriatrics and Gerontology, Cornell University Medical College, New York, NY 10021.
Szabo
P
P
Dyall
R
R
Weksler
M E
ME
D000375:Aging / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001483:Base Sequence; D001853:Bone Marrow / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D017931:DNA Primers; D005260:Female; D015870:Gene Expression; D015321:Gene Rearrangement; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D018398:Homeodomain Proteins; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D013950:Thymus Gland / Q000254:growth & development* / Q000276:immunology; D014185:Transplantation, Isogeneic
D017931:DNA Primers; D018398:Homeodomain Proteins; D011506:Proteins; D012333:RNA, Messenger; C064658:RAG-1 protein