Antigen receptor stimulation induces purifying selection against pathogenic mitochondrial tRNA mutations.

Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor-triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.

N6 -Methyladenosine Modification in Chronic Stress Response Due to Social Hierarchy Positioning of Mice.

Appropriately responding to stressful events is essential for maintaining health and well-being of any organism. Concerning social stress, the response is not always as straightforward as reacting to physical stressors, e.g., extreme heat, and thus has to be balanced subtly. Particularly, regulatory mechanisms contributing to gaining resilience in the face of mild social stress are not fully deciphered yet. We employed an intrinsic social hierarchy stress paradigm in mice of both sexes to identify critical factors for potential coping strategies. While global transcriptomic changes could not be observed in male mice, several genes previously reported to be involved in synaptic plasticity, learning, and anxiety-like behavior were differentially regulated in female mice. Moreover, changes in N6-methyladenosine (m6A)-modification of mRNA occurred associated with corticosterone level in both sexes with, e.g., increased global amount in submissive female mice. In accordance with this, METTL14 and WTAP, subunits of the methyltransferase complex, showed elevated levels in submissive female mice. N6-adenosyl-methylation is the most prominent type of mRNA methylation and plays a crucial role in processes such as metabolism, but also response to physical stress. Our findings underpin its essential role by also providing a link to social stress evoked by hierarchy building within same-sex groups. As recently, search for small molecule modifiers for the respective class of RNA modifying enzymes has started, this might even lead to new therapeutic approaches against stress disorders.

Lipid presentation by the protein C receptor links coagulation with autoimmunity.

Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.