Journal
IMMUNITY
Volume 43, Issue 5, Pages 884-895Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2015.10.002
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Funding
- NIH-NIAID [AI061093, AI071087, AI082713]
- INSERM, CEE EUROPAD-contract 7th Framework Program [201549]
- Assiociation Contre le Cancer
- Rubicon program, Netherlands Organization for Scientific Research
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Activation-induced cytidine deaminase (AID), the enzyme- mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID(+) immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.
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