Dnmt3a Mutations Limit Normal and Autoreactive CD4⁺ T Follicular Helper Responses and Attenuate T Cell-Driven Joint...

Area of Science:

• Immunology
• Genetics
• Rheumatology

Background:

• Somatic DNMT3A mutations are common in clonal hematopoiesis and linked to rheumatoid arthritis (RA).
• These mutations often reduce DNMT3A function, impacting epigenetic regulation.
• The role of these mutations in T cell-mediated autoimmunity is unclear.

Purpose of the Study:

• To investigate if DNMT3A mutations enhance the pathogenicity of autoreactive CD4+ T cells.
• To determine the impact of Dnmt3a loss-of-function on T follicular helper (Tfh) cell responses and autoimmune arthritis.

Main Methods:

• Utilized the KRN+ TCR-transgenic mouse model of autoimmune arthritis.
• Introduced Dnmt3a mutations using CRISPR-Cas9 and Cd4-cre recombination.
• Assessed Tfh responses, antibody production, and joint inflammation via competitive bone marrow chimeras, immunization, and T cell transfer.

Main Results:

• Loss of DNMT3A function in CD4+ T cells consistently reduced Tfh responses and IgG production.
• Mice with Dnmt3a-mutant autoreactive CD4+ T cells showed attenuated joint inflammation.
• Reduced systemic IL-6 and autoantibody levels were observed in mice receiving Dnmt3a-mutant T cells.

Conclusions:

• Wild-type DNMT3A supports Tfh responses in both immunization-driven and autoreactive settings.
• DNMT3A loss-of-function in CD4+ T cells limits autoreactive inflammation.
• Clinical associations in RA might involve other hematopoietic lineages or T cell functions beyond Tfh responses.