Selection of the B Cell Repertoire in Senescence

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 DESCRIPTION (provided by applicant): In old age, in both mice and humans, B lymphopoiesis is compromised and intrinsic B cell defects contribute to poor Ig isotype switch and somatic hypermutation. Old age causes poor B lymphopoiesis by interfering with: 1) pro-B/pre-B cell function; 2) development of common lymphoid progenitors (CLP); and 3) maintenance of lymphoid-biased hematopoietic stem cells (L-HSC). This contributes to alterations in B cell numbers and composition in the periphery and also changes the "read-out" of B cell antibody specificities. The latter can result in poor protection to infectious diseases. cells in old mice (and humans) are pro-inflammatory and express TNFa. In particular, the Age-associated B cells (ABC) in old mice are pro-inflammatory and represent a novel B cell subset which expands extensively in old age. By 2 years of age, ABC can constitute up to one- half of mature B cells in spleen and bone marrow. In old mice, TNFa diminishes peripheral B cell function by interfering with Ig isotype switching. In the bone marrow of old mice, ABC, via TNFa, induce apoptosis in B cell precursors. Moreover, those B cell precursors which are less affected by ABC in old mice express lower levels of the surrogate light chain (SLC). The SLC is a key constituent of the pre-B cell receptor (preBCR); compromise of the preBCR in old mice affects the "read-out" of the B cell antibody repertoire. This is seen as an increased frequency of B cells which are reactive with the bacterial epitope phosphorylcholine, are negative for the T15 idiotype, and are of low affinity. These "old-age" related anti-PC B cells produce less protective antibodies to pneumococci. In this proposal, we will test the role of pro-inflammatory B cells, including ABC, in down-regulating B lymphopoiesis at relatively late stages (pro-B/pre-B) as well as early stages (Common Lymphoid Progenitors [CLP]; hematopoietic stem cells [HSC]) of development (Specific Aims 1 and 2). Furthermore, we will determine effects of pro-inflammatory B cells, including ABC, in both altering the "read- out" of the B cell repertoire and inhibiting Ig isotype switch and somatic hypermutation in mature B cells (Specific Aim 3). Finally, we will test whether depletion of pro-inflammatory B cells and their subsets in old mice "rejuvenates" B cell development and "repairs" the functional B cell deficiencies seen in old age.