Journal
FRONTIERS IN IMMUNOLOGY
Volume 8, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2017.01076
Keywords
class switch recombination; CCCTC-binding factor; germline transcription; activation-induced deaminase; somatic hypermutation
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Funding
- Ministerio de Educacion, Cultura y Deporte [FPU-AP2009-1732]
- Ministerio de Economia y Competitividad [BES-2014-069525]
- Centro Nacional de Investigaciones Cardiovaculares (CNIC) [SAF2013-42767-R, SAF2016-75511-R]
- Fondo Europeo de Desarrollo Regional (FEDER)
- European Research Council [BCLYM-207844]
- Ministry of Economy, Industry and Competitiveness (MEIC)
- Pro CNIC Foundation
- Severo Ochoa Centre of Excellence [SEV-2015-0505]
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In response to antigenic stimulation B cells undergo class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) to replace the primary IgM/IgD isotypes by IgG, IgE, or IgA. CSR is initiated by activation-induced cytidine deaminase (AID) through the deamination of cytosine residues at the switch (S) regions of IgH. B cell stimulation promotes germline transcription (GLT) of specific S regions, a necessary event prior to CSR because it facilitates AID access to S regions. Here, we show that CCCTC-binding factor (CTCF)-deficient mice are severely impaired in the generation of germinal center B cells and plasma cells after immunization in vivo, most likely due to impaired cell survival. Importantly, we find that CTCF-deficient B cells have an increased rate of CSR under various stimulation conditions in vitro. This effect is not secondary to altered cell proliferation or AID expression in CTCF-deficient cells. Instead, we find that CTCF-deficient B cells harbor an increased mutation frequency at switch regions, probably reflecting an increased accessibility of AID to IgH in the absence of CTCF. Moreover, CTCF deficiency triggers premature GLT of S regions in naive B cells. Our results indicate that CTCF restricts CSR by enforcing GLT silencing and limiting AID access to IgH.
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