Dnmt3a mutations limit normal and autoreactive Tfh differentiation

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation, strongly associated with the activity of autoreactive CD4+ T cells. DNMT3A mutations are the most common somatic mutations found in the hematopoietic system of patients with rheumatoid arthritis. However, the role of DNMT3A in CD4+ T cells and CD4+ T follicular helper (Tfh) cells is poorly understood. Since somatic mutations are not identified in standard genome-wide association studies, somatic mutations impact on the etiology of diseases could be underestimated. Here, we thoroughly characterized and used the KRN+ splenocyte transfer model of autoimmune joint inflammation and inactivated Dnmt3a using CRISPR-Cas9 and standard Cre/loxP approaches. Experiments with competitive bone marrow (BM) chimeras identified a positive role for Dnmt3a in Tfh differentiation, which was validated by comparing mice with Dnmt3a mutations in CD4+ cells to animals with WT Dnmt3a. In conclusion, We identify that Dnmt3a mutations limit normal and autoreactive Tfh differentiation. ### Competing Interest Statement FW has received consulting fees from SmartCella Solutions, which is outside the scope of the submitted study.