Objective:

To test whether Dnmt3a mutations enhance the pathogenicity of autoreactive CD4+ T cells in rheumatoid arthritis (RA).

Approach:

• Model: Utilized the KRN+ TCR-transgenic transfer model of autoimmune arthritis to assess the impact of Dnmt3a mutations.
• Methods: Employed CRISPR-Cas9 or Cd4cre-mediated recombination to introduce Dnmt3a mutations, and evaluated Tfh responses, antibody production, and joint inflammation through competitive bone marrow chimeras and immunization with sheep red blood cells.

Key Findings:

• Loss of DNMT3A function in CD4+ T cells reduced Tfh responses and IgG production in the context of autoimmune arthritis.
• Mice with Dnmt3a-mutant autoreactive CD4+ T cells showed significantly attenuated joint inflammation compared to controls.
• Reduced systemic IL-6 and autoantibody levels were observed in the KRN+ transfer model with Dnmt3a mutations.

Interpretation:

Dnmt3a is essential for Tfh responses in both immunization-driven and autoreactive conditions, while loss of Dnmt3a function limits autoreactive inflammation.

Limitations:

• The study primarily focuses on Tfh-dependent responses and may not encompass other T cell functions or hematopoietic lineages.

Conclusion:

Dnmt3a mutations in CD4+ T cells limit autoreactive inflammation.