DNA (cytosine‐5)‐methyltransferase 3A (Dnmt3a) mutations limit normal and autoreactive CD4+ T follicular helper responses and attenuate T cell‐driven joint inflammation

Objective

Somatic DNMT3A mutations are the most common drivers of clonal hematopoiesis in patients with rheumatoid arthritis (RA) and have been associated with seropositive disease and increased inflammatory markers. These mutations are predominantly hypomorphic or dominant‐negative, reducing DNMT3A function. We tested whether Dnmt3a mutations enhance the pathogenicity of autoreactive CD4 ⁺ T cells.

Methods

Using the KRN ⁺ TCR‐transgenic transfer model of autoimmune arthritis, in which autoreactive CD4 ⁺ T follicular helper (Tfh) cells drive disease, we assessed the impact of Dnmt3a mutations introduced by CRISPR‐Cas9 or Cd4 ^cre ‐mediated recombination. Competitive bone marrow chimeras, immunization with sheep red blood cells, and autoreactive T‐cell transfer were used to evaluate Tfh responses, antibody production, and joint inflammation.

Results

Loss of DNMT3A function in CD4 ⁺ T cells consistently reduced Tfh responses and IgG production during both immunization‐driven and autoreactive activation. In the KRN ⁺ transfer model, mice receiving Dnmt3a ‐mutant autoreactive CD4 ⁺ T cells developed significantly attenuated joint inflammation, accompanied by reduced systemic IL‐6 and autoantibody levels.

Conclusion

Wild‐type Dnmt3a supports Tfh responses under both immunization‐driven and autoreactive conditions. Dnmt3a loss‐of‐function in CD4 ⁺ T cells limits autoreactive inflammation, suggesting that clinical associations in RA may reflect effects in other hematopoietic lineages or T cell functions beyond Tfh‐dependent responses.

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