Mitochondrial protein OPA1 is required for the expansion of effector CD8 T cells
Benjamin A.S. Willett,
Scott B. Thompson,
Vincent Chen,
Anza Dareshouri,
Conner L. Jackson,
Tonya Brunetti,
Angelo D’Alessandro,
Jared Klarquist,
Travis Nemkov,
Ross M. Kedl
Affiliations
Benjamin A.S. Willett
Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Scott B. Thompson
Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Vincent Chen
Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Anza Dareshouri
Department of Cell and Developmental Biology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Conner L. Jackson
Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Tonya Brunetti
Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Angelo D’Alessandro
Department of Biochemistry & Molecular Genetics, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Jared Klarquist
Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Travis Nemkov
Department of Biochemistry & Molecular Genetics, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
Ross M. Kedl
Department of Immunology and Microbiology, University of Colorado-Denver Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
Summary: Short-lived effector cells are characterized metabolically by a highly glycolytic state, driving energy and biomass acquisition, whereas memory-fated T cells have historically been described as meeting these requirements through mitochondrial metabolism. Here, we show that the mitochondrial protein optic atrophy 1 (OPA1) is critical for rapidly dividing CD8 T cells in vivo, the requirement for which is most pronounced in effector CD8 T cells. More specifically, OPA1 supports proper cell cycle initiation and progression and the viability and survival of CD8 T cells during clonal expansion. Use of mice deficient in the mitochondrial membrane fusion proteins Mitofusin 1 and 2 (MFN1/2) in both in vivo proliferation/differentiation assays and ex vivo metabolic analysis indicates that the requirement for OPA1 during cell division supersedes its role in mitochondrial fusion. We conclude that OPA1 is critical for the generation and accumulation of short-lived effector cells that arise during the response to infection.
