Somatically Diversified and Proliferating Transitional B Cells: Implications for Peripheral B Cell Homeostasis

Abstract

The peripheral B cell compartment in mice and humans is maintained by continuous production of transitional B cells in the bone marrow (BM). In other species however, including rabbits, B lymphopoiesis in the BM abates early in life and it is unclear how the peripheral B cell compartment is maintained. We identified transitional B cells in rabbits and classified them into T1 (CD24hiCD21lo) and T2 (CD24hiCD21+) B cell subsets. By neutralizing BAFF in vivo, we found an arrest in peripheral B cell development at the T1 B cell stage. Surprisingly, T1 B cells were present in GALT, blood and spleen of adult rabbits, long after B lymphopoiesis was arrested. T1 B cells were distinct from their counterparts in other species because they are proliferating and the Ig genes are somatically diversified. We designate these newly described cells as T1d B cells and propose a model in which they develop in GALT, self-renew, and continuously differentiate into mature B cells, and thereby maintain peripheral B cell homeostasis in adults in the absence of B lymphopoiesis.

Chemokine-Mediated B Cell Trafficking during Early Rabbit GALT Development

“…B cell shuttling of ICs and subsequent transfer of ICs to FDCs in mouse lymph nodes are dependent on complement, requiring C3 deposition on ICs, and B cell and FDC expression of the complement receptors CD21/35 (39, 41). Consistent with a similar B cell shuttling of bacterial cells in rabbit GALT, Yeramilli and Knight (42) observed C3 deposition in the follicles of conventional, but not germ-free ligated, appendix, and further found that lumenal bacteria were coated with C3 and IgA. Blocking CD21 binding/signaling with a CD21-Ig fusion protein and depleting C3 with cobra venom factor both inhibited B cell proliferation, demonstrating that antibody repertoire diversification in rabbit GALT is dependent on complement.…”

“…CCR7 might therefore act as a “default” receptor, mediating B cell migration to the B cell:T cell boundary after downregulation of CCR6 and CXCR5. Although antibody repertoire diversification in GALT is T cell-independent, in the sense of not being driven by cognate B cell-T cell interactions (35, 42), our results suggest that T cells contribute to the process. This is consistent with the observation that, during early follicle development, B cell proliferation occurs in the region of the follicle immediately adjacent to the T cell area (9, 12).…”

“…Signals such as these likely enhance Ag-independent activation and proliferation of rabbit appendix B cells during homing to the FDC network. FDC C4BP, for example, signals B cells via CD40, independently of CD40L expressed by activated T cells (45), which could account for the observation, by Yeramilli and Knight (42), that appendix B cell proliferation is inhibited by interruption of CD40-CD40L, but not B7-CD28, interaction. These authors also found that blocking CD21 signaling inhibited B cell proliferation, possibly reflecting an important role for FDC CD21L in stimulating antibody repertoire diversification in rabbit GALT.…”

“…Potential T cell factors include cytokines (IL-4, IFN-α and IFN-γ), CD40L and Plexin-B1 (47-49). Although CD40-CD40L signaling is required for B cell proliferation in rabbit GALT, as discussed above, activated T cells are not a required source of CD40L (42). The potential roles of other T cell factors in antibody repertoire diversification have not been studied.…”

Differences in Mouse and Human Nonmemory B Cell Pools

“…The mouse and other animal models provide important insights into human B cell development and disease (1, 2). Murine data show that B lineage committed progenitors arise from hematopoietic stem cells in the bone marrow (BM) and transit a series of developmentally sequential stages to produce immature B cells expressing surface IgM (3, 4).…”