A Division-Linked Mechanism for the Rapid Generation of Ig-Secreting Cells from Human Memory B Cells

Abstract

Memory B cells, when re-exposed to Ag and T cell help, differentiate into Ig-secreting cells (ISC) at the same time as maintaining a residual pool of non-Ig-secreting cells with memory capabilities. To investigate the mechanism underlying this dual process, we followed the fate of human B cells activated in vitro with the T cell-derived signals CD40 ligand (CD40L), IL-2, and IL-10 using CFSE to monitor cell division. A substantial number of ISCs detected by ELISPOT, intracellular Ig staining, and Ig secretion could be generated from memory but not naive B cells. The proportion of ISCs increased with successive cell divisions and was markedly enhanced by IL-10 at each division. Within ISCs, two distinct populations were detected after withdrawal of CD40L. The first had acquired the plasma cell marker CD38 and continued to proliferate despite the absence of CD40L. In contrast, the second population remained CD38−, ceased dividing, and underwent rapid apoptosis. The former most likely represent the immediate precursors of long-lived plasma cells, which preferentially home to the bone marrow in vivo, whereas the latter contain short-lived ISCs responsible for the initial Ab response to stimulation with Ag and T cell help. Taken together, the results point to a division-based mechanism responsible not only for regulating differentiation of short- and long-lived ISCs from memory B cells, but for preserving the memory B cell pool for reactivation upon subsequent Ag exposure.

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

“…1). A similar CD38 expression phenomenon was reported in studies using the two-step in vitro B cell differentiation culture system with IL-2, IL-10, CD40L, and BAFF in other studies (40,75).…”

B cells alter the phenotype and function of follicular‐homing CXCR5+ T cells

“…The observation that B cells promote an IL-10-producing phenotype in a large fraction of T FH cells is remarkable, given that IL-10 is an important factor in the differentiation of B cells to plasma cells [16,18,19,21], and underscores the importance of non-cognate T-B cell interactions in humoral immunity. The IL-10-secreting phenotype was stably maintained during T cell cloning, but secretion was, to a large extent, dependent on ICOS signaling, which is in agreement with previous reports [28][29][30][31].…”

“…Of interest, the fraction of IL-2-secreting cells also increased from <40% to >60% when T FH cells were The contribution of B cells to IL-10 production by T FH cells was particularly interesting, since IL-10 is known to play an essential role in Ig secretion by B cells [16,18,19,21]. This phenomenon was therefore analyzed further by comparing the ability of T FH cells to secrete IL-10 after co-culture with B cells in the presence or absence of T cell superantigen (Fig 4b).…”

“…The signals that drive B cell differentiation toward antibody-secreting plasma cells and long-lived memory B cells are diverse and include cytokines such as IL-10, as well as cell surface costimulatory molecules, including CD154 (CD40 ligand), CD70 and CD134 (OX40) [15][16][17][18][19][20][21]. It is presently unknown which mechanisms are utilized by T FH cells to provide help to B cells or how these signals are regulated.…”

Expansion of Functionally Immature Transitional B Cells Is Associated with Human-Immunodeficient States Characterized by Impaired Humoral Immunity

“…Human B cells were isolated using a B Cell Negative Isolation kit (Dynal Biotech). B cell subsets were isolated by sorting on a FACSVantage (BD Biosciences) after labeling purified total B cells with anti-CD24 and anti-CD38 mAb to identify CD24 high CD38 high , CD24 ϩ CD38 ϩ ("naive"), and CD24 ϩ CD38 Ϫ ("memory") B cells, respectively, or with anti-CD20 and anti-CD27 mAb to identify naive and memory B cells (31).…”