Dnmt3amutations limit normal and autoreactive Tfh differentiation

Abstract

AbstractRheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation, strongly associated with the activity of autoreactive CD4+ T cells.DNMT3Amutations 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 inactivatedDnmt3ausing CRISPR-Cas9 and standard Cre/loxP approaches. Experiments with competitive bone marrow (BM) chimeras identified a positive role forDnmt3ain Tfh differentiation, which was validated by comparing mice withDnmt3amutations in CD4+ cells to animals with WTDnmt3a. In conclusion, We identify thatDnmt3amutations limit normal and autoreactive Tfh differentiation.Key findings–Dnmt3amutations limit Tfh differentiation, which could contribute to reduced immune responses in individuals with somaticDNMT3Amutations.–Deep characterization of the KRN+ splenocyte transfer model defines a dynamic process leading to reproducible autoimmune joint inflammation.–The immuno-CRISPR (iCR) methodology can be used to test the role of candidate genes in disease models.