Single mutation tunes IRF4 function and mediates B cell character to ameliorate murine lupus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by abundant autoantibodies. B cells play a critical role in initiation and progress of SLE, showing immunotolerance loss, hyperactivity, and abnormal activation or maturation. Interferon regulatory factor 4 (IRF4) controls B cell differentiation; therefore, targeting IRF4 is a possible therapeutic. Here, we developed a mouse strain containing a single mutation in 123^th amino acid of IRF4 where lysine is replaced by arginine (IRF4^K123R). IRF4^K123R mutation in B cells did not alter IRF4 expression but markedly alleviated lupus through increasing B7-H1. IRF4^K123R mutation promoted follicular B cell differentiation and powered anti-inflammatory T cell phenotype. Mechanistically, IRF4^K123R mutation reinforced phosphorylated STAT3 binding and therefore enhanced B7-H1 transcription. These results indicate the specific role of IRF4 in B cells and lupus, providing a potential therapeutic target to combating SLE.