The number and production rates of pre-B-cells are reduced 4 fold in aged individuals, reflecting increased losses in pro-B-cell transit. Nonetheless, the number of B-cells entering the immature marrow pool remains similar to young adults, indicating that a larger proportion of pre-B-cells generated in aged mice survive. Further, the number of mature recirculating B-cells in the marrow increases with age, but without a corresponding increase in mature peripheral B-cells. Together, these findings lead us to hypothesize that age-associated shifts in the size and dynamics of key B lineage subsets yield alterations in the selective and/or homeostatic mechanisms that shape the B-cell pool. Therefore it is proposed to extend the understanding of these changes and their effects. In the first aim, the age and pattern of onset with which these changes occur will be determined. In addition, the temporal relationships of changes in newly forming versus mature marrow subsets will be explored.
The second aim will establish the relative contributions of B lineage-intrinsic vs. microenvironmental elements of these changes in B-cell dynamics. In the third aim, repertoire diversity in the immature B-cell pools of aged vs. young mice will be compared, in order to determine how increased proportional survival of immature B-cells affects selection within the emerging B-cell pool. In the fourth aim, the life span, homing characteristics, and repertoire diversity of recirculating mature B-cells in aged marrow will be determined, to assess the identity and functional significance of this population.
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