Maintenance of B-cell memory by long-lived cells generated from proliferating precursors

Abstract

A basic feature of T-cell dependent antibody responses is the generation of memory: on a second contact with an antigen a secondary response is produced in which somatically mutated antibodies with increased affinity are synthesized. Memory can persist for long periods of time. This has classically been ascribed to the generation of long-lived memory B cells. However, it is also possible that persisting antigen, on which memory may depend, maintains a population of cycling memory cells under continuous selection or continuously recruits newly generated B cells into the memory B-cell compartment. To discriminate between these mechanisms we have now directly analysed the proliferative activity in the memory B-cell compartment of the mouse by measuring bromodeoxyuridine incorporation in vivo. We show that after an initial phase of extensive proliferation after primary immunization, memory cells can persist in the organism for extended periods of time in the absence of cell division.

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

“…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). The surviving memory blasts most likely revert to a quiescent state to serve as the memory cell pool, which can be reactivated upon subsequent Ag exposure (12,15,16,59). Our in vitro findings that CD38 Ϫ blasts undergo rapid apoptosis after removal of CD40L (Figs.…”

“…Thus, whereas plasma cells are mitotically quiescent and terminally differentiated, memory B cells are capable of consecutive phases of stimulation, expansion, selection, and generation of effector cells (7,8,(12)(13)(14). As a consequence, the population of memory B cells is maintained and even enhanced by frequent exposure to Ag (12,15), giving it the attributes of a "stem" type cell for the plasma cell lineage (16).…”

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

“…B mem cells are maintained with no or very slow cycling 39 , so we asked whether the iMB cells are cycling in vivo . BrdU-pulsed iGB cells were transferred into irradiated mice and their kinetics were analysed.…”

Estimating average cellular turnover from 5–bromo–2'–deoxyuridine (BrdU) measurements

“…The base analogue 5-bromo-29-deoxyuridine (BrdU) can be administered via drinking water and substitutes for thymidine in newly synthesized DNA. BrdU 1 cells can be easily detected by flow cytometry, and BrdU labelling has been widely used to study lymphocyte kinetics in animals (Gratzner 1982;Penit & Vasseur 1988;Forster et al 1989;Forster & Rajewsky 1990;Rocha et al 1990;Schittek & Rajewsky 1990;Tough & Sprent 1994Dolbeare 1995;Zimmerman et al 1996;Mohri et al 1998;Bonhoeffer et al 2000;Kovacs et al 2001). Cellular turnover rates in man have also been studied by the administration of deuterated glucose ( 2 H-glucose), which leads to deuterium being incorporated into the DNA of dividing cells (Macallan et al 1998;Hellerstein 1999;Hellerstein et al 1999;McCune et al 2000;Mohri et al 2001;Ribeiro et al 2002a,b).…”