Apoptotic cell–induced, TLR9-dependent AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans

The transcription factor AhR modulates immunity at multiple levels. Here we report phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of interleukin 10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in murine systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice and an increased AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance.