T-Bet+ IgM Memory Cells Generate Multi-lineage Effector B Cells

Abstract

SUMMARY Immunoglobulin M (IgM) memory cells undergo differentiation in germinal centers following antigen challenge, but the full effector cell potential of these cells is unknown. We monitored the differentiation of enhanced yellow fluorescent protein (eYFP)- labeled CD11c+ and CD11cneg T-bet+ IgM memory cells after their transfer into naive recipient mice. Following challenge infection, many memory cells differentiated into IgM-producing plasmablasts. Other donor B cells entered germinal centers, down- regulated CD11c, underwent class switch recombination, and became switched memory cells. Yet other donor cells were maintained as IgM memory cells, and these IgM memory cells retained their multi-lineage potential following serial transfer. These findings were corroborated at the molecular level using immune repertoire analyses. Thus, IgM memory cells can differentiate into all effector B cell lineages and undergo self-renewal, properties that are characteristic of stem cells. We propose that these memory cells exist to provide long-term multi-functional immunity and act primarily to maintain the production of protective antibodies.

T‐bet+ memory B cells: Generation, function, and fate

“…39,41,49,76 Similarly, T-bet + B cells are rare in healthy human blood but present in greater numbers following vaccination or infection: T-bet + B cells expand in frequency following live virus vaccination, are overrepresented in individuals with HIV, HCV, or malaria, and represent the primary HIV Env-specific memory B cell population in viremic individuals. T-bet-expressing B cells are exceedingly rare in young mice in the absence of infectious challenge, 27 but antigen-specific T-bet + B cells can be readily identified in the spleen following infection with E. muris or a diverse array of viruses.…”

“…35,41,46,76 Few studies address their role in secondary immune responses, but E. muris-reactive T-bet + B cells are required to mount an IgG response during re-infection. 35,41,46,76 Few studies address their role in secondary immune responses, but E. muris-reactive T-bet + B cells are required to mount an IgG response during re-infection.…”

“…Based on existing evidence, they are persistent, 27,28 exhibit some degree of multipotency, 41 and appear to contribute to the continuous development of autoreactive antibodysecreting cells. Based on existing evidence, they are persistent, 27,28 exhibit some degree of multipotency, 41 and appear to contribute to the continuous development of autoreactive antibodysecreting cells.…”

“…[6][7][8][9][10] Analogous broad categories also exist among antigen-experienced cells of the B lineage-memory B cells (Bmem) and antibodysecreting plasma cells (PC)-and reports of subdivisions within these groups have emerged in the last several years. 26,[35][36][37][38][39][40][41] In this article, we first review the discovery and general characteristics of T-bet + memory B Summary B cells expressing the transcription factor T-bet have emerged as participants in a number of protective and pathogenic immune responses. [17][18][19][20] Within this context, a B cell subset expressing the transcription factor T-bet has been the focus of increasing interest in the last several years, reflected by numerous commentaries and dedicated overview volumes.…”

“…lished data). IgM + T-bet + B cells were assumed to selfrenew based upon their persistence and were thus hypothesized to maintain a stem cell-like differentiation state 41. IgG1 + T-betcells could similarly be "imprinted"by T-bet expression during their development and may no longer require active expression of the transcription factor to maintain their current functionality.It is also likely that T-bet + B cells, at least on a population level, are capable of differentiating into multiple types of effector cells.A recent study by Kenderes et al 41 identified an E. muris-inducedIgM + T-bet + B cell population that was maintained long term and could give rise to a number of B cell lineage subsets, such as bone marrow and splenic antibody-secreting cells, germinal center B cells, and IgG + memory B cells.…”