Naive B Lymphocytes Undergo Homeostatic Proliferation in Response to B Cell Deficit

Abstract

Naive peripheral B cells are maintained in sufficient numbers and diversity to mount effective immune responses against infectious agents. However, the size and repertoire of this B cell pool is constantly diminished by normal cell turnover and Ag activation. Homeostatic (Ag-independent) proliferation in response to B cell depletion is one mechanism to compensate for this cell loss. We have used purified CFSE-labeled B cells and an adoptive transfer model system to show that immature and mature B cells divide in a variety of B cell-deficient (scid, xid, IL-7−/−, and sublethally irradiated) hosts. Homeostatic B cell proliferation is T cell independent, and B cells that have replicated by this mechanism retain the antigenic phenotype of naive B cells. Replication is significantly reduced in B cell-sufficient normal or B cell-reconstituted immunodeficient recipients by the action of competing mature follicular B cells. Using xid mice and transcription factor knockouts, we show that the activation signal(s) that lead to homeostatic B cell proliferation require Bruton’s tyrosine kinase; however, c-Rel, a Bruton’s tyrosine kinase-induced NF-κB/Rel transcription factor critical for Ag and mitogen stimulation, is dispensable, indicating the uniqueness of this activation pathway. Survival and replication signals can also be separated, because the transcription factor p50 (NF-κB1), which is required for the survival of peripheral B cells, is not necessary for homeostatic replication. Homeostatic B cell proliferation provides an Ag-independent mechanism for the maintenance and expansion of naive B cells selected into the mature B cell pool.

γδ T Cell Homeostasis Is Controlled by IL-7 and IL-15 Together with Subset-Specific Factors

“…Thus, in secondary lymphoid organs, ␥␦ T cell homeostasis is controlled, in part, by the size of both the ␣␤ T cell pool, which defines availability of specific cytokines, and the ␥␦ T cell pool, which defines availability of additional ␥␦ T cell ligands. Together with previous reports documenting lymphopenia-induced homeostatic expansion of ␣␤ T cells (9), NKT cells (13), NK cells (12), and B cells (14), the present findings provide further support to the notion that the lymphocyte repertoire is not static, but subject to continuous dynamic changes, partially determined by the symbiotic relationship and interdependence among the various cell types with regard to overlapping resources available in limited supply. The physiological significance of lymphopenia-induced homeostatic proliferation remains a matter of speculation.…”

“…Similar approaches have been used to define the homeostatic requirements for NK cells, NKT cells, and B cells. For homeostatic expansion in lymphopenic mice, NK cells require IL-15 (12), NKT cells require IL-15 (and less IL-7) but not the Ag-presenting CD1d molecule (13), and B cells require Btk-mediated signals but not IL-7 (14).…”

The c-Rel transcription factor and B-cell proliferation: a deal with the devil

“…The reduced mitogen-induced proliferation is due to arrested cellcycle progression in c-relÀ/À B cells . However, c-Rel is not required for antigen-independent B-cell proliferation that occurs during B-cell depletion (Cabatingan et al, 2002). Consistent with the B-cell proliferation and survival defects, c-rel null mice have small/irregular germinal centers and reduced marginal zone B cells (Cariappa et al, 2000).…”

Impaired B‐1 and B‐2 B cell development and atypical splenic B cell structures in IL‐7 receptor‐deficient mice

“…3B). Such a scenario is also supported by, firstly, increased rates of B cell proliferation and terminal differentiation in B lymphopenic mice [34][35][36] and, secondly, activation and normal serum IgM levels after transfer of small numbers of resting B cells into immunodeficient mice [37].…”