Mettl8 programs Tcf1+CXCR5+ T cells in autoimmune disease and tumor by mediating Tcf1 mRNA m3C modification and Tcf1-bound chromatin loops

In the tumor microenvironment (TME), the active tertiary lymphoid structure (TLS) plays a crucial role in fostering the reactivation of naïve or memory cells, leading to the expansion of effector cells. However, an excessive reinvigoration of T cells can result in autoimmune-like diseases, such as those observed in immune checkpoint blockade (ICB) therapy. Here, we have identified that the gene encoding RNA methyltransferase Mettl8 is highly expressed in inflammatory CD4+ CXCL13+ TFH cells of autoimmune patients. Surprisingly, the genetic deletion of Mettl8 in mice resulted in a reduced autoimmune phenotype in helper CD4 cells and slowed tumor growth through increased activation/effector response in CD8+ T cells. Mechanistically, Mettl8 is found to imprint m3C modification, stabilizing Tcf1 mRNA, and simultaneously interacts with Tcf1 protein to co-bind specific genome loops for genomic reorganization, as revealed by Hi-C analysis. These findings suggest that targeting Mettl8 promotes antitumor immunity while preventing the occurrence of autoimmune diseases. Notably, pharmacological inhibition of sumoylation-stabilizing Mettl8 protein has shown efficacy in compromising autoimmune CXCL13+ TFH specialization and function. In conclusion, these findings underscore the dual regulatory elements of the Mettl8-Tcf1 complex as a promising target for tumor immunotherapy, offering protection against autoimmune diseases.