Co-option of retrotransposons promotes antibody diversification.

Activation-induced cytidine deaminase (AID) accomplishes somatic hypermutation (SHM) of VH(D)JH genes in germinal center B cells for antibody diversification and affinity maturation. How AID specifically targets VH(D)JH remains unclear. We report the discovery of LINE-1 (L1) retrotransposons upstream to many VH genes in the immunoglobulin locus. These L1s are evolutionarily old, truncated, and retrotransposition dead. Recombined VH promoters generate long, strong antisense RNAs encoding upstream L1s, triggering the human silencing hub (HUSH) complex and AID recruitment, which we term L1-driven SHM. We show that L1-driven SHM occurs in vivo using HUSH conditional knockout mice and engineered mice with VH genes devoid of upstream L1s. Insertion of transcriptionally active L1s at non-immunoglobulin loci endogenously lacking upstream L1s promotes off-target SHM. We demonstrate that old retrotransposons serve physiological roles, and our findings reveal how B cells co-opted an anti-retrotransposon silencing mechanism to promote antibody diversity. In doing so, we established a new link between cell-intrinsic innate and adaptive immunity.