Abstract
Defects in the expression of either BAFF (B cell activating factor) or BAFF-R impairs B cell development beyond the immature, transitional type-1 stage and thus, prevents the formation of follicular and marginal zone B cells, whereas B-1 B cells remain unaffected. The expression of BAFF-R on all mature B cells might suggest a role for BAFF-R signaling also for their in vivo maintenance. Here, we show that, 14 days following a single injection of an anti-BAFF-R mAb that prevents BAFF binding, both follicular and marginal zone B cell numbers are drastically reduced, whereas B-1 cells are not affected. Injection of control, isotype-matched but non-blocking anti-BAFF-R mAbs does not result in B cell depletion. We also show that this depletion is neither due to antibody-dependent cellular cytotoxicity nor to complement-mediated lysis. Moreover, prevention of BAFF binding leads to a decrease in the size of the B cell follicles, an impairment of a T cell dependent humoral immune response and a reduction in the formation of memory B cells. Collectively, these results establish a central role for BAFF-BAFF-R signaling in the in vivo survival and maintenance of both follicular and marginal zone B cell pools.
Highlights
The pool of peripheral B cells is continuously replenished by newly-formed immature B cells generated in the bone marrow
Beyond its essential role in allowing the developmental progression from immature type 1 (T1) cells into T2–T3 and mature B cells, we formally demonstrate the essential role of the BAFF-BAFF receptor (BAFF-R) signaling in the long-term survival and homeostasis of mature B-2 and marginal zone B cells
Characterization of anti-BAFF-R monoclonal antibodies A mixture of un-transfected and mouse BAFF-R-expressing Y3 rat myeloma cells was used to screen supernatants of individual hybridomas generated as described in Materials and Methods
Summary
The pool of peripheral B cells is continuously replenished by newly-formed immature B cells generated in the bone marrow. Following several steps of antigen-independent differentiation and depending upon successful rearrangement of the corresponding genes and expression of the B cell receptor (BCR) protein on their surface, only about 20% of the newly-generated bone marrow B cells migrate to the spleen as immature B cells [3,4,5,6,7]. These cells are characterized by a short half-life of about 2–4 days and upon further differentiation steps develop into mature, naıve B cells. The surrounding stromal micro-environment, the presence of appropriate growth factors, as well as their ability to respond to them, are all crucial players in the final maturation steps of developing B cells
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