Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by Rapid Up-Regulation of B7-1 and B7-2

115

The VH4 genes expressed by both resting and in vivo-activated subepithelial (SE) B cells from human tonsils were studied. Resting SE B cells were subdivided according to the presence (IgDlow) or absence (IgM-only) of surface IgD. CD27 was abundant on activated SE B cells and low on resting IgM-only B cells. Resting IgDlow SE B cells could be subdivided into CD27low and CD27high cell fractions. Resting IgDlow SE B cells displayed VH4 genes with a substantial number of mutations (13/29 of the molecular clones were mutated), whereas 25/26 of the clones from resting IgM-only SE B cells were unmutated. Moreover, mutated VH4 genes were detected mainly within the CD27high cell fraction of the IgDlow SE B cells. Several identical unmutated VH4DJH sequences (11/32) were found in different molecular clones from resting IgM-only SE B cells, suggesting local cellular expansion. Both unmutated (14/25) and mutated (11/25) sequences were found in μ transcripts of activated SE B cells. Extensive mutation was observed in the γ transcripts of activated SE B cells. Therefore, SE B cells are heterogeneous, being comprised of B cells with mutated Ig VH4 genes, that are Ag-experienced B cells, and a subset of B cells with unmutated VH4 genes that are either virgin cells or cells driven by Ags that did not induce or select for V gene mutations.

“…1). Phenotypically, these B cells were identical to the memory B cells of the tonsillar SE area described previously (25,35) and will be referred to as activated SE B cells.…”

Section: Hcdr3 Analysismentioning

confidence: 52%

Heterogeneity of Tonsillar Subepithelial B Lymphocytes, the Splenic Marginal Zone Equivalents

Dono

Zupo²,

Leanza

et al. 2000

115

“…In contrast, the CD38 Ϫ ISCs, being CD40L dependent, will only survive and contribute Ig as long as Ag and T cell help are both available. Given that stimulation of activated T cells requires Ag presentation by memory B cells (1,42), successful Ag clearance would act as a feedback mechanism limiting memory B cell expansion and further development of both short-and long-lived ISCs, although limited differentiation of the CD38 ϩ ISCs already formed would continue. In vivo studies have revealed that the number of Ag-specific B cells present at the conclusion of a secondary immune response is reduced 10-to 50-fold compared with the peak of the response, indicative of apoptosis of the majority of memory blasts after Ag clearance (12).…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with this finding was the demonstration of 5-to 30-fold more IgM, IgG, and IgA secreted by memory compared with naive B cells under these stimulation conditions (Table I). The CD38 ϩ cells generated in these cultures displayed reduced expression of CD20, but maintained high levels of CD39 (data not shown), thereby distinguishing them from GC B cells (17,42).…”

Section: Il-10 Promotes Cd40l-stimulated Memory But Not Naive B Celmentioning

confidence: 99%

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

Tangye

Avery

Hodgkin

2003

152

216

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.

“…Phenotypically distinct subsets of human B cells can also be identified in different lymphoid tissues. Thus, immature B cells are CD19 ϩ CD27 Ϫ CD10 ϩ IgM ϩ IgD Ϫ , while naive B cells are CD19 ϩ CD27 Ϫ IgM low IgD high , and memory B cells are CD19 ϩ CD27 ϩ and express IgM, IgG, or IgA (2,(12)(13)(14)(15). Human transitional B cells, however, remain poorly characterized, although their existence is suggested by the recent demonstration of a population of cells in peripheral blood (PB) distinguishable from mature B cells on the basis of a CD24 high CD38 high phenotype (16,17).…”

mentioning

confidence: 99%

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

Cuss

Avery

Cannons

et al. 2006

177

188

X-linked lymphoproliferative disease (XLP) is a severe immunodeficiency associated with a marked reduction in circulating memory B cells. Our investigation of the B cell compartment of XLP patients revealed an increase in the frequency of a population of B cells distinct from those previously defined. This population displayed increased expression of CD10, CD24, and CD38, indicating that it could consist of circulating immature/transitional B cells. Supporting this possibility, CD10+CD24highCD38high B cells displayed other immature characteristics, including unmutated Ig V genes and elevated levels of surface IgM; they also lacked expression of Bcl-2 and a panel of activation molecules. The capacity of CD24highCD38high B cells to proliferate, secrete Ig, and migrate in vitro was greatly reduced compared with mature B cell populations. Moreover, CD24highCD38high B cells were increased in the peripheral blood of neonates, patients with common variable immunodeficiency, and patients recovering from hemopoietic stem cell transplant. Thus, an expansion of functionally immature B cells may contribute to the humoral immunodeficient state that is characteristic of neonates, as well as patients with XLP or common variable immunodeficiency, and those recovering from a stem cell transplant. Further investigation of transitional B cells will improve our understanding of human B cell development and how alterations to this process may precipitate immunodeficiency or autoimmunity.