New markers for murine memory B cells that define mutated and unmutated subsets

Anderson, Shannon M.; Tomayko, Mary M.; Ahuja, Anupama; Haberman, Ann M.; Shlomchik, Mark J.

doi:10.1084/jem.20062571

Cited by 239 publications

(328 citation statements)

References 57 publications

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“…Memory B cells share the expression of several receptors involved in regulating the renewal of stem cell populations (26), so ligands for these receptors may replace BLyS as key survival factors. TLR stimulation is required for activation of human B cells (27) and leads to TACI up-regulation on murine FO and MZ cells (24) (29,30) and supports the notion of heterogeneity among memory B cells (2,31). We also show heterogeneity within the B1 B cell compartment, because BLyS inhibition spared PerC B1 cells but left a residual B1 subset in the spleen that functionally resembles PerC B1 cells.…”

Section: Resultssupporting

confidence: 51%

“…Together, these findings show that memory B cells and natural antibodysecreting cells are BLyS-independent and suggest that these pools can be separately manipulated. Although memory populations are a small proportion of total B cells, they turn over more slowly than their naïve precursors and afford protective immunity upon secondary antigen challenge (2,3). Primary immune responses also generate long-lived plasma cells (LLPC), which persist indefinitely and maintain systemic antibody levels.…”

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confidence: 99%

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BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact

Scholz

Crowley

Tomayko

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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We have used an inhibiting antibody to determine whether preimmune versus antigen-experienced B cells differ in their requisites for BLyS, a cytokine that controls differentiation and survival. Whereas in vivo BLyS inhibition profoundly reduced naïve B cell numbers and primary immune responses, it had a markedly smaller effect on memory B cells and long-lived plasma cells, as well as secondary immune responses. There was heterogeneity within the memory pools, because IgM-bearing memory cells were sensitive to BLyS depletion whereas IgG-bearing memory cells were not, although both were more resistant than naïve cells. There was also heterogeneity within B1 pools, as splenic but not peritoneal B1 cells were diminished by anti-BLyS treatment, yet the number of natural antibody-secreting cells remained constant. Together, these findings show that memory B cells and natural antibodysecreting cells are BLyS-independent and suggest that these pools can be separately manipulated.

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Section: Resultssupporting

confidence: 51%

mentioning

confidence: 99%

BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact

Scholz

Crowley

Tomayko

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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161

148

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“…First, memory B cells with relatively high-affinity B-cell antigen receptors are able to rapidly capture low levels of secondary antigen and present this antigen to the cognate T FH memory cells. In this context, increased levels of CD80 and MHC class II on memory B cells could contribute to efficient activation of T FH memory cells (28 (21).…”

Section: Discussionmentioning

confidence: 99%

Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells

Ise

Inoue

McLachlan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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In primary humoral responses, B-cell lymphoma 6 (Bcl6) is a master regulator of follicular helper T (T FH ) cell differentiation; however, its activation mechanisms and role in memory responses remain unclear. Here we demonstrate that survival of CXCR5 + T FH memory cells, and thus subsequent recall antibody response, require Bcl6 expression. Furthermore, we show that, upon rechallenge with soluble antigen Bcl6 in memory T FH cells is rapidly induced in a dendritic cell-independent manner and that peptide:class II complexes (pMHC) on cognate memory B cells significantly contribute to this induction. Given the previous evidence that antigen-specific B cells residing in the follicles acquire antigens within minutes of injection, our results suggest that memory B cells present antigens to the cognate T FH memory cells, thereby contributing to rapid Bcl6 reexpression and differentiation of the T FH memory cells during humoral memory responses.immunological memory | antibody production T he development of high-affinity B-cell memory is essential in most effective vaccines that are in use today. Because most protein antigens require T-cell help to induce B-cell responses, understanding the mechanisms by which memory T and B cells are generated and maintained, as well as how their swift activation is executed, is of fundamental importance for vaccine development.In primary immune responses, it is widely accepted that among several differentiated helper T-cell subsets follicular helper CD4 T cells (T FH cells) are the major subset to deliver help to B cells (1). T FH cells express CXC-chemokine receptor 5 (CXCR5), the chemokine receptor for the B-cell homing chemokine CXCL13. Surface expression of CXCR5 enables T FH cells to migrate into B-cell follicles, where they provide help to B cells to form germinal centers. In addition, T FH cells are needed for the crucial affinitymaturation process of B cells in germinal centers, whereby Agspecific B cells undergo repeated rounds of somatic hypermutation and positive selection by T FH cells to rapidly evolve high-affinity somatically mutated B-cell receptors. B-cell lymphoma 6 (Bcl6) has recently been identified as a T FH lineage regulator (2-4); it is highly expressed by T FH cells and is required for their development. According to the current view, during a primary response Bcl6 expression by T cells is induced by priming with dendritic cells (5-7) and ICOS is a key coreceptor molecule for induction of Bcl6 (5, Although the importance of Bcl6 and its expression kinetics in naïve T-cell differentiation have been well elucidated, its role and activation mechanisms in T FH memory cells still remain obscure. Hence, in this paper we first focus upon the roles of Bcl6, demonstrating its importance for maintenance of T FH memory cells. Then, we show that Bcl6 in memory T FH cells was rapidly induced upon rechallenge with soluble antigen and that this response was mainly mediated through antigen presentation by the cognate memory B cells. Given the good association between Bcl6 wi...

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“…Moreover, there is no defi nitive marker for B mem cells in mice. B7.1 (CD80) 25 and CD38 (ref. 26) are useful but not B mem -specifi c markers.…”

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confidence: 99%

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

et al. 2011

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In response to T cell-dependent antigens, B cells proliferate extensively to form germinal centres (GC), and then differentiate into memory B (B mem ) cells or long-lived plasma cells (LLPCs) by largely unknown mechanisms. Here we show a new culture system in which mouse na ï ve B cells undergo massive expansion and isotype switching, and generate GC-phenotype B (iGB) cells. The iGB cells expressing IgG1 or IgM / D, but not IgE, differentiate into B mem cells in vivo after adoptive transfer and can elicit rapid immune responses with the help of cognate T cells. Secondary culture with IL-21 maintains the proliferation of the iGB cells, while shifting their in vivo developmental fate from B mem cells to LLPCs, an outcome that can be reversed by withdrawal of IL-21 in tertiary cultures. Thus, this system enables in vitro manipulation of B-cell fate, into either B mem cells or LLPCs, and will facilitate dissection of GC-B cell differentiation programs.

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New markers for murine memory B cells that define mutated and unmutated subsets

Cited by 239 publications

References 57 publications

BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact

BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact

Memory B cells contribute to rapid Bcl6 expression by memory follicular helper T cells

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

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