Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory

Kaji, Tomohiro; Ishige, Akiko; Hara, Masaki; Taka, Junko; Hijikata, Atsushi; Kubo, Masato; Nagashima, Takeshi; Takahashi, Yoshimasa; Kurosaki, Tomohiro; Okada, Mariko; Ohara, Osamu; Rajewsky, Klaus; Takemori, Toshitada

doi:10.1084/jem.20120127

Cited by 247 publications

(272 citation statements)

References 61 publications

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“…A, EZH2 inhibition induces a gene set that is heavily enriched for memory cell genes in DLBCL cell lines. RNA-seq data from KARPAS-422 (EZH2-mutant GCB), Farage (EZH2 WT GCB), SU-DHL-5 (EZH2 WT GCB), and TMD8 (EZH2 WT ABC) treated with 1 mmol/L tazemetostat (TAZ) for 4 days was analyzed using GSEA (Broad Institute) for enrichment of the GSE11961 memory B-cell versus germinal center B-cell gene set (31). NES and FDR scores are indicated.…”

Section: Discussionmentioning

confidence: 99%

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EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased Bcell maturation and a greater dependence on B-cell activation signaling.

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Section: Discussionmentioning

confidence: 99%

“…Normalized RNA-seq values from samples with and without tazemetostat treatment were run through the algorithm. Altered genes were compared against gene sets found to be induced in the transition from germinal center B-cells to memory B-cells (31).…”

Section: Rna-seqmentioning

confidence: 99%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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“…TEa TCR transgenic mice (CD45.2/CD45.2 or CD45.1/CD45.2) (31), Bcl6-YFP reporter mice (17), CD11c-DTR transgenic mice (32), B1-8 hi IgH knock-in mice (33), and IL-21 hCD2 Bac Tg reporter (15) mice were bred on-site. Bcl6 flox mice were independently generated using the same strategy as in a previous study (34) and were bred with Rosa-CreERT2 mice (purchased from Taconic) and TEa TCR transgenic mice.…”

Section: Methodsmentioning

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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“…Memory B lymphocytes expressing switched isotypes of antibodies and IgM‐expressing memory B lymphocytes have been identified. Memory B lymphocytes undergoing further affinity maturation in germinal center reactions, and memory B lymphocytes independent of germinal centers, have been described 179, 180…”

Section: Memory B Lymphocytes Of the Bone Marrowmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

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Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory

Abstract: B cell memory is generated along two fundamentally distinct cellular differentiation pathways.

Cited by 247 publications

References 61 publications

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

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

Immunological memories of the bone marrow

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