Homeostatic Mechanisms Controlling B Lymphopoiesis in Aging

Generally, the number of peripheral B cells does not change significantly throughout life as generation of new B cells in the Bone Marrow (BM) is balanced by death of B cells in the periphery, a process refers to as cellular homeostasis. This balance between cell input and output within the B cell compartment is important for the integrity of the organism and for mounting an effective immune response. Yet, cellular homeostasis adapts to physiological changes. A good example for such adaptation is the dramatic changes in the B cell compartment that occur with aging, where B cell production declines and long-lived memory B cells accumulate in the periphery. However, these changes in B cell homeostasis are associated with reduced responsiveness to vaccination and increases morbidity.

So far, the mechanism by which cellular homeostasis is established is still unknown. Studies in our lab have demonstrated a feedback mechanism by which peripheral B cells suppress B lymphopoiesis in aging. In these studies we showed that removal of peripheral B cells reactivates B lymphopoiesis in the BM and rejuvenates the peripheral compartment in old mice and humans.

In the present study we aim to identify molecular mechanisms and/or molecules that mediate this cross-talk mechanism. To test this, we used an in vitro bone marrow culture system to grow B lineage cells from progenitors. We found that B cells purified from old mice suppressed B lymphopoiesis when cultured in direct contact or in transwell system. To support these findings in an in vivo setting, we transferred old splenic B cells into young hCD20Tg mice that were treated for B cell depletion. Bone marrow analysis for B lymphopiesis revealed a significant suppression relative to control hCD20Tg mice that were injected with young splenic B cells. Furthermore, we found that B lymphopoiesis is effectively suppressed in the presence of sera from old mice. These findings confirm that old B cells inhibit B lymphopoiesis and that this inhibition is mediated by a secreted soluble factor. Applying proteomics approach to analyze soluble factors in serum we identified Insulin-like Growth Factor 1 (IGF-1) as a potential molecule whose reduced level in aging may mediate this suppression effect. Preliminary studies supported this possibility.

Collectively, our results suggest that in aged individuals B lymphopoiesis is subjected to homeostatic feedback mechanisms imposed by mature B cells in the peripheral compartment.