THE B-CELL REPERTOIRE OF AGED MICE

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Aging is accompanied by numerous alterations in B cell repertoire expression and responsiveness. Although B cells of aged mice respond normally to T/H dependent antigens and the overall numbers and diversity of B cells is maintained, the repertoire of B cells responsive to certain antigens is altered and the capacity to generate high affinity memory B cells is compromised. This is a proposal to continue our long-standing investigation of the cellular and molecular basis of these aging associated alterations in the B cell component of the immune response. Although the number of newly generated B cells is not markedly reduced in aged mice the pathway of B cell development is altered such that the population of mature pre B cells is decreased several fold. To determine if this is due to a decrease in clonal expansion during pre B cell development, in Specific Aim 1 we will assess the recurrence of unique H chain V regions in cells within various developmental B cell subsets obtained from the marrow of individual femora. We will also use single cell PCR to determine whether pre B cell maturation may be accelerated by premature L chain expression. To determine if a decrease in clonal elimination (tolerance) in aged mice contributes to the maintenance of normal numbers of newly generated B cells, in Specific Aim 2 we will determine if there is a decrease in slg receptor mediated elimination of newly generated B cells that express H chains encoded by V(H)81X-D-J(H) rearrangements. Finally, to assess the potential contribution of alterations in memory progenitors to the decrease in the generation of high affinity somatically mutated memory B cells, in Specific Aim 3 we will evaluate, clonally, the capacity of memory progenitors obtained from naive and immunized aged mice to generate memory B cells and accumulate somatic mutations in vitro.