Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection

Chen, Chao; Zhai, Sulan; Zhang, Le; Chen, Jingjing; Long, Xuehui; Qin, Jun; Li, Jianhua; Huo, Ran; Wang, Xiaoming

doi:10.1084/jem.20171815

Cited by 28 publications

(36 citation statements)

References 45 publications

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“…In contrast, DNMT3A is downregulated . Conditional deletion of DNMT1 or UHRF1 (ubiquitin‐like with PHD and RING finger domains 1) have demonstrated that DNA methylation can take place in the germinal center B cells. DNMT1 hypomorphic mice have defective germinal center responses .…”

Section: Changes In Dna Methylation Throughout B Cell Differentiationmentioning

confidence: 99%

Epigenetic regulation of B cell fate and function during an immune response

Zhang

Good-Jacobson

2019

Immunological Reviews

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Summary The humoral immune response requires coordination of molecular programs to mediate differentiation into unique B cell subsets that help clear the infection and form immune memory. Epigenetic modifications are crucial for ensuring that the appropriate genes are transcribed or repressed during B cell differentiation. Recent studies have illuminated the changes in DNA methylation and histone post‐translational modifications that accompany the formation of germinal center and antibody‐secreting cells during an immune response. In particular, the B cell subset‐specific expression and function of DNA methyltransferases and histone‐modifying complexes that mediate epigenome changes have begun to be unravelled. This review will discuss the recent advances in this field, as well as highlight critical questions about the relationship between epigenetic regulation and B cell fate and function that are yet to be answered.

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Section: Changes In Dna Methylation Throughout B Cell Differentiationmentioning

confidence: 99%

Epigenetic regulation of B cell fate and function during an immune response

Zhang

Good-Jacobson

2019

Immunological Reviews

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“…For surface staining, cells were isolated from spleen or lymph nodes, incubated with indicated antibodies on ice for 30 min, and washed with staining buffer (2% FBS in PBS with 0.1% NaN 3 and 50 mM EDTA). For intracellular staining, cells were fixed with 1% paraformaldehyde in PBS and permeabilized with cold methanol as previously described (Chen et al, 2018). Data were acquired on a Beckman Cytoflex and analyzed with FlowJo 10 software.…”

Section: Flow Cytometry and Cell Sortingmentioning

confidence: 99%

“…Unlike H3K27me3 modification, which occurs mainly near the gene promoter region, H3K36 methylation, especially H3K36me2/3, decorates the gene body region and associates with active transcription (Wagner and Carpenter, 2012). Our previous study revealed that Nsd2 expressed in B cells is required for GC B cell selection by regulating adhesive interaction between GC B cells and follicular dendritic cells (Chen et al, 2018). However, the role of H3K36me in T cell differentiation has not been investigated yet.…”

Section: Introductionmentioning

confidence: 97%

Histone methyltransferase Nsd2 is required for follicular helper T cell differentiation

Long

Zhang

et al. 2019

Journal of Experimental Medicine

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Follicular helper T (Tfh) cells provide essential help for humoral immune response. Transcriptional factor Bcl6 is the master regulator for Tfh generation and is induced very early after T cell activation in a CD28-dependent manner, but how CD28 signal promotes Bcl6 early expression remains unknown. Here we found that CD28 signal quickly induces expression of the H3K36me2 methytransferase Nsd2, which is required for Bcl6 expression as early as the first cell division after T cell activation. Nsd2 deficiency in T cells leads to decreased Bcl6 expression, impaired Tfh generation, compromised germinal center response, and delayed virus clearance. Ectopic Bcl6 expression rescues the Tfh defect of Nsd2 KO cells. ICOS signal is dispensable for early Nsd2 induction but required for sustained Nsd2 expression, which is critical for Tfh maintenance. Overexpression of Nsd2 increases Bcl6 expression and enhances Tfh generation; 4-mo-old mice even develop spontaneous Tfh. Overall, our study reveals Nsd2 as a critical epigenetic regulator for Tfh differentiation.

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“…Germinal centers are the primary location of affinity maturation, a cyclic process by which B cells mutate their immunoglobulin genes, compete for antigen and T cell help, and undergo clonal expansion following positive selection (Cyster and Allen, 2019;Mesin et al, 2016). Previous studies have shown that accumulation of affinity-enhancing mutations is critical for eventual control of viremia during chronic LCMV infection (Chen et al, 2018;Chou et al, 2016). However, the delayed production of neutralizing antibody during chronic LCMV infection (Battegay et al, 1993;Eschli et al, 2007) suggests that the process of affinity maturation is dysregulated, an alteration that may also occur during other chronic infections (Doria-Rose et al, 2014;Kinchen et al, 2018;Minamitani et al, 2015;Wu et al, 2015).…”

Section: Affinity Maturation Is Impaired During Chronic Infectionmentioning

confidence: 99%

“…However, despite these challenges, GC still form during chronic infection (Barnett et al, 2016;Daugan et al, 2016) and antibodies have been shown to diversify over time during chronic HIV and HCV infections (Doria-Rose et al, 2014;Kinchen et al, 2018;Wu et al, 2015), suggesting ongoing GC activity. Moreover, despite generally smaller GCs during chronic infection, affinity-matured antibodies produced as a result of the GC response exert partial but critical control of viral replication and, in some cases, lead to viral control (Chen et al, 2018;Chou et al, 2016;Doria-Rose et al, 2014;Kinchen et al, 2018). Additionally, non-neutralizing antibodies are required to partially contain infection in many cases (Barnett et al, 2016;Hangartner et al, 2006;Horwitz et al, 2017;Richter and Oxenius, 2013;Straub et al, 2013) and can apply selective pressure for viral escape and evolution in some settings (Doria-Rose et al, 2014;Kinchen et al, 2018;Wu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

Staupe

Vella

Manne

et al. 2019

Preprint

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Chronic viral infections disrupt B cell responses leading to impaired affinity maturation and delayed control of viremia. Previous studies have identified early pre-germinal center (GC) B cell attrition but the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, we used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virusspecific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, these studies define GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

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Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection

Abstract: Germinal center (GC) B cell response is critical for pathogen protection. Chen et al. find that Uhrf1 is up-regulated by the c-Myc–AP4 axis and plays an essential role in GC B cell expansion and affinity maturation.

Cited by 28 publications

References 45 publications

Epigenetic regulation of B cell fate and function during an immune response

Epigenetic regulation of B cell fate and function during an immune response

Histone methyltransferase Nsd2 is required for follicular helper T cell differentiation

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

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