Cross-Linking Surface Ig Delays CD40 Ligand- and IL-4-Induced B Cell Ig Class Switching and Reveals Evidence for Independent Regulation of B Cell Proliferation and Differentiation

Rush, James S.; Hasbold, Jhagvaral; Hodgkin, Philip D.

doi:10.4049/jimmunol.168.6.2676

Cited by 34 publications

(20 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To address this idea, αIgM was added to both the LPS plus IL-4 and αCD40 plus IL-4 activations. Surprisingly, the addition of αIgM suppressed the class switch recombination observed in both activations, which has also been observed by others in cells stimulated through the CD40 receptor (Rush et al, 2002;Thomas et al, 2007). We show here that this was not due to lack of AID, since AID was expressed in all activations.…”

Section: Discussionsupporting

confidence: 58%

Activation-induced deaminase-mediated class switch recombination is blocked by anti-IgM signaling in a phosphatidylinositol 3-kinase-dependent fashion

Heltemes-Harris

Gearhart

Ghosh

et al. 2008

Molecular Immunology

View full text Add to dashboard Cite

Activation-induced deaminase (AID) is expressed in activated B lymphocytes and initiates somatic hypermutation and class switch recombination. To determine if different stimuli affect the expression and function of AID, we monitored AID activity in murine B cells stimulated ex vivo with various ligands. AID was rapidly expressed at both the RNA and protein levels following stimulation with LPS, LPS plus IL-4, and anti-CD40 plus IL-4, but was delayed after stimulation with anti-IgM plus IL-4. By day 4, AID was expressed in all groups; however, cells stimulated with anti-IgM plus IL-4 did not undergo switch recombination. These cells expressed normal levels of γ1 germline transcripts, implying that the γ1 switch region was accessible. Furthermore, switching was suppressed by the addition of anti-IgM to cells stimulated with LPS plus IL-4 or anti-CD40 plus IL-4, even though AID was expressed. The lack of class switch recombination could be reversed by inhibition of phosphatidylinositol 3-kinase (PI3K). This suggests that activation through the B cell receptor induces PI3K, which interferes with the function of AID.

show abstract

Section: Discussionsupporting

confidence: 58%

Activation-induced deaminase-mediated class switch recombination is blocked by anti-IgM signaling in a phosphatidylinositol 3-kinase-dependent fashion

Heltemes-Harris

Gearhart

Ghosh

et al. 2008

Molecular Immunology

View full text Add to dashboard Cite

show abstract

“…A long-standing correlation exists between a prolonged G1 phase that enhances the differentiation potential and a shortened G1 phase that diminishes it (Kato and Sherr, 1993;Carroll et al, 1995;Johnson et al, 1993). However, there is experimental evidence in a variety of cell types, including lymphocytes (Rush et al, 2002;Lea et al, 2003), which show that these processes can be separated and need not proceed simultaneously (Brown et al, 2003). Experiments here are consistent with the idea that Fbxo7 promotes the differentiation of pro-B cells: overexpression of Fbxo7 decreased CD43, which is downregulated as B cell mature, and reduction of Fbxo7 levels increased its expression.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells

Meziane¹,

Randle²,

Nelson³

et al. 2011

Development

View full text Add to dashboard Cite

Research Article 2175 IntroductionDuring the cell cycle, ubiquitin-mediated proteolysis provides a swift and precise means to regulate the abundance of cell cycle regulatory proteins, including cyclins and cyclin-dependent kinase (Cdk) inhibitors. This mechanism for regulating the turnover of proteins is mediated through ubiquitin ligases, which transfer ubiquitin to target proteins, enabling their timely destruction (Hershko, 1997;Hershko and Ciechanover, 1998;Nakayama and Nakayama, 2006;Reed, 2006;Reed, 2003). E3 ubiquitin-ligases promote the specific attachment of poly-ubiquitin chains, which then triggers proteolysis by the 26S proteasome. SCF-type (Skp1-Cullin-F-box) E3 ubiquitin ligases are multi-subunit complexes that consisting of Skp1, Cullin, Rbx1 and an F-box protein (FBP) (Ang and Wade, 2005;Deshaies, 1999;Jackson and Eldridge, 2002;Nakayama and Nakayama, 2005;Vodermaier, 2004). It is the FBP, which has a crucial role in specifically recruiting the target substrate, usually directed by post-translational modification of the substrate (Cenciarelli et al., 1999;Hermand, 2006;Ho et al., 2008;Jin et al., 2004;Winston et al., 1999). In cell cycle regulation, several FBPs that regulate G1-S phase regulators have been intensively studied. These include the prototypical S-phase kinaseassociated protein 2 (Skp2, also known as Fbxl1) and the F-box and WD repeat domain containing 7 (Fbxw7) that, respectively, regulate the levels of the Cdk inhibitors cyclin E and cyclindependent kinase inhibitor 1B (CDKN1B; also known as and hereafter referred to as p27). In addition, three FBPs -Fbxo4, Another FBP that interacts with G1-S regulatory proteins is Fbox protein 7 (Fbxo7). In contrast to the destabilising effects of other FBPs, Fbxo7 acts as a specific assembly factor for cyclin DCdk6 complexes. Fbxo7 interacts directly with both Cdk6 and p27, and cooperatively increases cyclin D3 interactions with Cdk6 in vitro (Laman et al., 2005). In vivo, Fbxo7 overexpression in immortalised murine fibroblasts leads to their Cdk6-dependent transformation. These cells had increased levels of cyclin D-Cdk6 complexes and E2F activity, and formed tumours in athymic nude mice (Laman et al., 2005). Many mitogen and cytokine signalling pathways converge on cyclin D-Cdk activity, which -when overstimulated -promotes oncogenesis. Because of its Cdk6-dependent transforming activity, we propose that Fbxo7 functions as an oncogene.In U2OS and NIH3T3 cells, Fbxo7 has shown selectivity for Cdk6 over Cdk2 and Cdk4. Although the biochemical properties of Cdk4 and Cdk6 are similar, more-recent studies have indicated that differences can be discerned in their selective binding to cofactors (Sugimoto et al., 1999;Laman et al., 2005), preference for phosphorylation sites in pRb in vitro (Takaki et al., 2005), sensitivities to INK4 family members (Tourigny et al., 2002;Jones et al., 2007) and in vivo partnering with D-type cyclins (Ely et al., 2005). Also, in studies of knockout mice, tissue-specific defects are seen: Cdk4-knockout mice have impair...

show abstract

“…4 This finding adds to the growing evidence for unique signaling pathways regulating AID expression through the BCR and other surface receptors. 38,39 These studies have shown that signaling through the BCR delays AID expression and down-regulates certain AID-induced processes, such as class-switching, while having no effect on total transcript and protein levels. Furthermore, costimulation of both the BCR and TLR-4 was enough to dampen CSR in a phosphatidylinositol 3-kinase-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

View full text Add to dashboard Cite

IntroductionA fundamental hallmark of humoral immunity is the ability to produce class-switched antibodies that have enhanced affinity for antigen. This process, termed affinity maturation, allows clonally selected B cells to refine their response to theoretically target any antigen with high specificity. After activation, B cells mutate the immunoglobulin (Ig) locus in a process known as somatic hypermutation (SHM). 1 Mutated clones that have acquired increased affinity for antigen preferentially expand over their low-affinity counterparts. The selection process occurs in the germinal center (GC), a transient microenvironment that forms in secondary lymphoid tissue shortly after antigen exposure. 2 The GC provides a competitive setting for B cells whereby ineffectual clones are actively cleared from the system via apoptosis, although the processes that govern this selection still remain vague.SHM and class switch recombination (CSR) are initiated by the enzyme activation-induced cytidine deaminase (AID), 3,4 which deaminates cytidines to uridines specifically at the Ig locus. 5-10 AID-generated uridines are then engaged by various DNA repair pathways that either lead to the generation of point mutations in the antibody variable region or recombinogenic events that lead to CSR. AID Ϫ/Ϫ mice lack mutations at their Ig locus and are incapable of producing class-switched antibodies. 4 Interestingly, these mice were previously shown to harbor an abnormally high proportion of splenic GC B cells. 11 This phenotype is also recapitulated in humans with AID deficiencies. 3 Although a link between reduced gut immunity (resulting from an inability to produce mucosal IgA) and peripheral GC formation was hypothesized to account for these abnormalities, this remains to be conclusively proven, and the possibility of a B cell-intrinsic effect that could explain the profound expansion of GC B cells has not been examined.GC B cells represent a unique lymphoid compartment of actively proliferating cells where numerous apoptotic factors must synergize to induce the elimination of nonproductive clones. Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, 12-17 and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells. 13,[23][24][25][26] Recent evidence has implicated AID as a fundamental contributor to the genetic aberrations that lead to these disease phenotypes. 24,[27][28][29] Given the importance of apoptosis as a parameter for both GC B-cell selection and lymphomagenesis, we investigated the relationship between AID-induced DNA mutation and cell death to understand how this enzyme may impinge on survival and death within the GC niche. Here we report that many of the potentially harmful AID-induced genetic alterations may indeed lead to the death of these cells within the GC. Methods Mice...

show abstract

Cross-Linking Surface Ig Delays CD40 Ligand- and IL-4-Induced B Cell Ig Class Switching and Reveals Evidence for Independent Regulation of B Cell Proliferation and Differentiation

Cited by 34 publications

References 57 publications

Activation-induced deaminase-mediated class switch recombination is blocked by anti-IgM signaling in a phosphatidylinositol 3-kinase-dependent fashion

Activation-induced deaminase-mediated class switch recombination is blocked by anti-IgM signaling in a phosphatidylinositol 3-kinase-dependent fashion

Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Contact Info

Product

Resources

About