Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance

作者：Cantaert Tineke; Schickel Jean Nicolas; Bannock Jason M; Ng Yen Shing; Massad Christopher; Oe Tyler; Wu Renee; Lavoie Aubert; Walter Jolan E; Notarangelo Luigi D; Al Herz Waleed; Kilic Sara Sebnem; Ochs Hans D; Nonoyama Shigeaki; Durandy Anne; Meffre Eric^*

来源：Immunity, 2015, 43(5): 884-895.

DOI：10.1016/j.immuni.2015.10.002

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.

• 出版日期2015-11-17