In aged mice, low surrogate light chain promotes pro‐ B ‐cell apoptotic resistance, compromises the P re BCR checkpoint, and favors generation of autoreactive, phosphorylcholine‐specific B cells

• Published in: Aging cell Vol. 14; no. 3; pp. 382 - 390
• Main Authors: Ratliff, Michelle, Alter, Sarah, McAvoy, Kelly, Frasca, Daniela, Wright, Jacqueline A., Zinkel, Sandra S., Khan, Wasif N., Blomberg, Bonnie B., Riley, Richard L.
• Format: Journal Article
• Language: English
• Published: 01.06.2015
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12302

Summary In aged mice, new B‐cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B‐cell precursors with higher levels of the surrogate light chain (SLC) proteins (λ5/VpreB) and (ii) λ5 low B‐cell precursors generate new B cells which show increased reactivity to the self‐antigen/bacterial antigen phosphorylcholine (PC). Pro‐B cells in old bone marrow as well as pro‐B cells from young adult λ5‐deficient mice are resistant to cytokine‐induced apoptosis (TNFα; TGFβ), indicating that low λ5 expression in pro‐B cells is sufficient to cause increased survival. Transfer of TNFα‐producing ‘age‐associated B cells’ (ABC; CD21/35 − CD23 − ) or follicular (FO) B cells from aged mice into RAG‐2 KO recipients led to preferential loss of λ5 high pro‐B cells, but retention of λ5 low , apoptosis‐resistant pro‐B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of λ5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis, mediated in part by TNFα‐producing B cells, results in preferential loss of SLC high pro‐B cells within the bone marrow. Further B‐cell development then occurs via an ‘SLC low ’ pathway that not only impairs B‐cell generation, but promotes autoreactivity within the naïve antibody repertoires in the bone marrow and periphery.