IL-21 and BAFF/BLyS Synergize in Stimulating Plasma Cell Differentiation from a Unique Population of Human Splenic Memory B Cells

Abstract

Both constitutive Ig secretion by long-lived plasma cells (PC) and the recurrent differentiation of memory (mem) B cells into PC contribute to the maintenance of serologic mem. However, the relative contribution of each is unknown. In this study, we describe a novel population of human postswitched mem B cells that rapidly differentiate into PC and thus contribute to serologic mem. These IgG+ B cells reside in the region of human spleen analogous to the murine marginal zone and have not previously been examined. These cells are highly responsive to IL-21 in the context of CD40 stimulation. Uniquely, IgG+ marginal zone analog B cells are exquisitely sensitive to the combination of IL-21 and B cell-activating factor belonging to the TNF family (BAFF/BLyS) that synergize in the absence of further costimulation to induce up-regulation of B lymphocyte-induced maturation protein-1 and drive PC differentiation. Other cytokine combinations are not active in this regard. This is the first demonstration that this unique population of mem B cells can respond specifically and exclusively to IL-21 and BAFF/BLyS by differentiating into IgG-secreting PC, and thus contributing to serologic mem in an Ag-independent manner.

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

“…The finding that BAFF induced plasmablast differentiation from a CD27 2 IgD 2 DN subpopulation represents a new functional response identified for these cells that exist in higher abundance in the blood of SLE patients. Prior studies have shown that MZA B cell subsets in the spleen, defined as postswitch IgG + memory B cells, were IL-21 and BAFF responsive and could differentiate into plasmablasts (27). However, the CD27 + memory B cells in peripheral blood demonstrated in this study that we show are responsive to BAFF are phenotypically distinct from MZA B cells, excluding the possibility that they are recirculating MZA B cells (data not shown).…”

“…1). As shown in this and other studies, CD40L costimulation with IL-21 induces robust plasmablast differentiation from both naive and memory B cells (19,27,114). Stimulation of naive B cells with BAFF or anti-IgM alone or each in the presence of IL-2 and IL-21, however, does not induce significant proliferation or differentiation.…”

“…For example, IL-21 induces maximum proliferation and produce Abs when costimulated with CD40L, but induces apoptosis when costimulated with anti-IgM in mice and human (19,26). IL-21 and BAFF synergize in stimulating plasma cell differentiation from human splenic memory B cells (27). IL-2 is predominately a T cell-derived cytokine that promotes B cell proliferation and enhances the effects of IL-21 in inducing plasmablast by CD40L stimulation (19,28,29).…”

B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans

“…Therefore BAFF-R-deficient B cells respond to polyclonal activation like transitional B cells from cord blood and may develop into memory and plasma cells when activated appropriately. However, this does not exclude the possibility that BAFF-R function is needed for the development of plasma cells from IgGϩ postmemory B cells residing in the marginal zone of human spleen (29).…”

“…The late onset of disease symptoms itself is also remarkable, and thus BAFF-R deficiency may be regarded as the first immunodeficiency diagnosed primarily in individuals who are in their second half of life. Impaired B-cell-related immunity is an important factor for the increased susceptibility to infections in elderly persons [29]. The search for factors contributing to the immunological defects in this increasing patient population is of great socioeconomic importance, given the current demographic development in the western hemisphere.…”