Antigen receptor stimulation drives selection against pathogenic mtDNA variants that dysregulate lymphocyte responses

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Abstract Pathogenic mitochondrial (mt)DNA molecules can exhibit heteroplasmy in single cells and cause a range of clinical phenotypes, although their contribution to immunity is poorly understood. Here, in mice carrying heteroplasmic C5024T in mt-tRNA Ala – that impairs oxidative phosphorylation – we found a reduced mutation burden in peripheral T and B memory lymphocyte subsets, compared to their naïve counterparts. Furthermore, selection diluting the mutation was induced in vitro by triggering T and B cell antigen receptors. While C5024T dysregulated naïve CD8 + T cell respiration and metabolic remodeling post-activation, these phenotypes were partially ameliorated by selection. Analogous to mice, peripheral blood memory T and B lymphocyte subsets from human MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) patients – carrying heteroplasmic A3243G in mt-tRNA Leu – displayed a reduced mutation burden, compared to naïve cells. In both humans and mice, mtDNA selection was observed in IgG + antigen-specific B cells after SARS-CoV-2 Spike vaccination, illustrating an on-going process in vivo . Taken together, these data illustrate purifying selection of pathogenic mtDNA variants during the oxidative phosphorylation checkpoints of the naïve-memory lymphocyte transition. Highlights In human MELAS patients (A3243G in mt-tRNA Leu ) and a related mouse model (C5024T in mt-tRNA Ala ), T and B memory subsets displayed a reduced mtDNA mutation burden compared to their naïve counterparts. Selection was observed in antigen-specific IgG + B cells after SARS-CoV-2 Spike protein vaccination. T and B cell antigen receptor stimulation triggered purifying selection in vitro , facilitating mechanistic studies of mtDNA selection. Heteroplasmic pathogenic mutations in mtDNA dysregulated metabolic remodeling after lymphocyte activation and reduced macrophage OXPHOS capacity.

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