Doctor of Philosophy (PHD)
Microbiology and Immunology (Medicine)
Date of Defense
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
Fifth Committee Member
Sixth Committee Member
Senescent mice show diminished B lymphopoiesis as well as alterations in mature B cell compartments. Within both spleen and bone marrow (BM), aged mice show ~5-10 fold increases in "age associated B cells (ABC)", which is a normally minor mature B cell subset that lacks surface expression of CD21/35 and CD23. This population, through senescence acquired secretion of TNF-alpha, can induce apoptosis in pro-B cells directly, as well as indirectly through the bone marrow. Adoptive transfer experiments suggest ABC contribute to a pro-inflammatory environment within the bone marrow of aged mice. Old FO and FO-like BM B cells produce TNFà while young do not, but both ages contain an IL-10 producing subset, which can abrogate the effects of TNFà on pro-B cells. The increased ABC relative to the FO-like B cells in the bone marrow showed significant correlation to the loss of B cell recursors (BCP) in old mice in vivo. This in turn contributes to the loss in B lymphopoiesis seen in old age. Aged pre-B and pro-B cells have reduced expression of the surrogate light chain (SLC; VpreB, Lambda5), part of the pre-BCR complex. In both aged mice and ABC adoptive transfer recipients, pro-B cells show decreased expression of SLC. BCP that show little or no SLC expression are resistant to TNFà induced apoptosis. Pro-B cells express a "pro-BCR?" complex that contains cadherin 17 (cadh17) and SLC. Low expression of cadh17/SLC in pro-B cells is associated with increased phosphorylation of pro-apoptotic Bim, leading to its inactivation and degradation. Crosslinking cadh17 on the surface of SLClo pro-B cells restores apoptotic sensitivity to TNF-alpha by reducing the levels of phospho-Bim. Loss of SLC also alters the susceptibility of pro-B cells to a very different apoptotic stimulus, TGF?, at the signal transduction and nuclear translocation stages. These results suggest that alterations in B cell composition in old age contribute to an inflammatory bone marrow microenvironment, which preferentially targets pro-B cells that express high levels of SLC, inducing apoptosis and reducing the pool of pro-B cells in aged mice to low SLC expressing cells. This loss of high SLC expressing pro-B cells likely compromises B cell development at the pro-B to pre-B transition.
pro-BCR; aging; Age-associated B cells; Cadherin 17
Ratliff, Michelle, "Old Age Imposes Selection of Precursor B Cells by a Surrogate Light Chain Dependent Mechanism" (2013). Open Access Dissertations. 958.