Induced Expression of Murine γ2a by CD40 Ligation Independently of IFN-γ

Collins, John T.; Shi, Jian; Burrell, Bryna E.; Bishop, D. Keith; Dunnick, Wesley A.

doi:10.4049/jimmunol.177.8.5414

Cited by 5 publications

(4 citation statements)

References 42 publications

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“…We devised an RT-PCR that would measure the quantity of chimeric Iγ2aCγ1 transcripts by a direct comparison to the endogenous Iγ2aCγ2a germline transcripts, which should be at the same levels in all transgenic cells. As we have reported (23), transgenic, wild type Iγ2aCγ2a (Igh a allele) germline transcripts are more abundant (8.6-fold for line 820 and 15-fold for line 336) than endogenous (Igh b allele) germline transcripts (Fig. 4D).…”

Section: Resultssupporting

confidence: 72%

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The Role of Germline Promoters and I Exons in Cytokine-Induced Gene-Specific Class Switch Recombination

Dunnick

Shi

Holden

et al. 2011

The Journal of Immunology

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Germline transcription precedes class switch recombination (CSR). The promoter regions and I exons of these germline transcripts include binding sites for activation- and cytokine-induced transcription factors, and the promoter regions/I exons are essential for CSR. Therefore, it is a strong hypothesis that the promoter/I exons regions are responsible for much of cytokine-regulated, gene-specific CSR. We tested this hypothesis by swapping the germline promoter and I exons for the murine γ1 and γ2a H chain genes in a transgene of the entire H chain C-region locus. We found that the promoter/I exon for γ1 germline transcripts can direct robust IL-4–induced recombination to the γ2a gene. In contrast, the promoter/I exon for the γ2a germline transcripts works poorly in the context of the γ1 H chain gene, resulting in expression of γ1 H chains that is <1% the wild-type level. Nevertheless, the small amount of recombination to the chimeric γ1 gene is induced by IFN-γ. These results suggest that cytokine regulation of CSR, but not the magnitude of CSR, is regulated by the promoter/I exons.

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Section: Resultssupporting

confidence: 72%

“…As we reported, the CD40L expressed by insect cells is a potent inducer of CSR to γ2a (much stronger than anti-CD40 antibodies—ref. 23), and so we observe as much or more IμCγ2a transcripts in CD40L alone or in CD40L+IFN-γ compared to LPS+IFN-γ (Fig. 3A, second set of panels).…”

Section: Resultsmentioning

confidence: 69%

The Role of Germline Promoters and I Exons in Cytokine-Induced Gene-Specific Class Switch Recombination

Dunnick

Shi

Holden

et al. 2011

The Journal of Immunology

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“…Plasma and bone marrow cells were harvested from wild-type and Cox-2 −/− mice 28 days following infection. Plasma antibody titers were assayed for VV-specific IgG2a, the predominant isotype for viral neutralization and clearance [18, 19]. IgG2a titers were significantly reduced in Cox-2 deficient mice compared to wild-type (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…CD4+ T cells drive the germinal center reaction in the spleen generating memory B cells and long-lived plasma cells responsible for secreting antibodies [21]. T cell production of IFN-γ in germinal centers generates class-switched B cells that produce Th1 antibodies, IgG2a being the most important for viral neutralization and clearance [18, 19]. Therefore, we hypothesized that mice receiving chronic doses of Cox-2 selective inhibitors would have reduced frequencies of T cells producing IFN-γ.…”

Section: Resultsmentioning

confidence: 99%

Chronic inhibition of cyclooxygenase-2 attenuates antibody responses against vaccinia infection

Bernard

Bancos

Chapman

et al. 2010

Vaccine

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Generation of optimal humoral immunity to vaccination is essential to protect against devastating infectious agents such as the variola virus that causes smallpox. Vaccinia virus (VV), employed as a vaccine against smallpox, provides an important model of infection. Herein, we evaluated the importance cyclooxygenase-2 (Cox-2) in immunity to VV using Cox-2 deficient mice and Cox-2 selective inhibitory drugs. The effects of Cox-2 inhibition on antibody responses to live viruses such as vaccinia have not been previously described. Here, we used VV infection in Cox-2 deficient mice and in mice chronically treated with Cox-2 selective inhibitors and show that the frequency of VVspecific B cells was reduced, as well as the production of neutralizing IgG. VV titers were approximately 70 times higher in mice treated with a Cox-2 selective inhibitor. Interestingly, Cox-2 inhibition also reduced the frequency of IFN-γ producing CD4 + T helper cells, important for class switching. The significance of these results is that the chronic use of NSAIDs, and other drugs that inhibit Cox-2 activity or expression, blunt the ability of B cells to produce anti-viral antibodies, thereby making vaccines less effective and possibly increasing susceptibility to viral infection. These new findings support an essential role for Cox-2 in regulating humoral immunity.

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Requirements for the natural killer cell-mediated induction of IgG1 and IgG2a expression in B lymphocytes

Gao

Jennings

Yuan

2008

International Immunology

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Upon interaction with resting B lymphocytes, IL-2-propagated NK cells can initiate the process of Ig constant region switch recombination (CSR) by inducing germ line transcripts for gamma2a (Igamma2a) as well as increased levels of mRNA for activation-induced cytidine deaminase enzyme. Whereas both these processes are necessary for CSR, they are not sufficient because the cells do not proceed to the expression of mature mRNA for gamma2a (VDJCgamma2a). In addition, NK cells can also upregulate mRNA for the T-box transcription factor (T-bet) in B cells without being able to induce further differentiation. Using transgenic B cells with B cell receptor specificity for nitrophenol (NP), we have now shown that NP-Ficoll-stimulated B cells can be induced by NK cells to express IgG2a as well as IgG1 presumably due to the completion of the process of switch recombination. The inductive ability of NK cells does not require IFN-gamma but does require signals transmitted via CD48 by direct cell contact. In addition, NP-Ficoll on its own can induce proliferation of antigen-specific B cells as well as germ line transcripts of gamma1; however, expression of VDJCgamma1 mRNA also requires NK cell interaction with B lymphocytes. Therefore, in the presence of antigen, NK cells can provide a necessary signal that substitutes for cytokines in the induction of IgG2a as well as IgG1 expression. This in vitro analysis provides a mechanistic basis for understanding the documented NK cell effects on T-independent B cell responses in vivo.

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Induced Expression of Murine γ2a by CD40 Ligation Independently of IFN-γ

Cited by 5 publications

References 42 publications

The Role of Germline Promoters and I Exons in Cytokine-Induced Gene-Specific Class Switch Recombination

The Role of Germline Promoters and I Exons in Cytokine-Induced Gene-Specific Class Switch Recombination

Chronic inhibition of cyclooxygenase-2 attenuates antibody responses against vaccinia infection

Requirements for the natural killer cell-mediated induction of IgG1 and IgG2a expression in B lymphocytes

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