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 (V-H) 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 V-H 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 V-H genes. These findings suggest that thymic function can regulate both Rag-1 gene expression and VII gene use by bone marrow B-cell precursors.