The IL-21-TET2-AIM2-c-MAF pathway drives the T follicular helper cell response in lupus-like disease

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves T follicular helper (T_FH ) cell-mediated humoral immune responses. Absent in melanoma 2 (human AIM2 and murine Aim2) is a well-known component of the inflammasome in the innate immune system. Surprisingly, we observed that in SLE patients, upregulated levels of AIM2 expression were found in peripheral blood and skin lesions, with the highest levels detected in T_FH -like cells. In the CD4^cre Aim2^fl/fl conditional knockout mice, a markedly reduced T_FH cell response was observed, with significantly lower levels of serum autoantibodies and proteinuria, as well as profoundly reduced renal IgG deposition in pristane-induced lupus mice. Mechanistically, IL-21 was found to recruit hydroxymethyltransferase ten-eleven translocation 2 (TET2) to the AIM2 promoter, resulting in DNA demethylation and increased transcription of AIM2. In addition, AIM2 could regulate c-MAF expression to enhance IL-21 production, which consequently promoted T_FH cell differentiation. Our results have identified a role of AIM2 in promoting the T_FH cell response and further revealed that the IL-21-TET2-AIM2-c-MAF signalling pathway is dysregulated in lupus pathogenesis, which provides a potential therapeutic target for SLE.