Mitochondrial Pyruvate Carrier 1 Promotes Peripheral T Cell Homeostasis through Metabolic Regulation of Thymic Development
Andrew G. Ramstead,
Jared A. Wallace,
Soh-Hyun Lee,
Kaylyn M. Bauer,
William W. Tang,
H. Atakan Ekiz,
Thomas E. Lane,
Ahmad A. Cluntun,
Matthew L. Bettini,
June L. Round,
Jared Rutter,
Ryan M. O’Connell
Affiliations
Andrew G. Ramstead
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Jared A. Wallace
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Soh-Hyun Lee
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Kaylyn M. Bauer
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
William W. Tang
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
H. Atakan Ekiz
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Thomas E. Lane
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
Ahmad A. Cluntun
Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA
Matthew L. Bettini
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA
June L. Round
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
Jared Rutter
Department of Biochemistry, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Howard Hughes Medical Institute, University of Utah, Salt Lake City, UT 84112, USA
Ryan M. O’Connell
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Corresponding author
Summary: Metabolic pathways regulate T cell development and function, but many remain understudied. Recently, the mitochondrial pyruvate carrier (MPC) was identified as the transporter that mediates pyruvate entry into mitochondria, promoting pyruvate oxidation. Here we find that deleting Mpc1, an obligate MPC subunit, in the hematopoietic system results in a specific reduction in peripheral αβ T cell numbers. MPC1-deficient T cells have defective thymic development at the β-selection, intermediate single positive (ISP)-to-double-positive (DP), and positive selection steps. We find that early thymocytes deficient in MPC1 display alterations to multiple pathways involved in T cell development. This results in preferred escape of more activated T cells. Finally, mice with hematopoietic deletion of Mpc1 are more susceptible to experimental autoimmune encephalomyelitis. Altogether, our study demonstrates that pyruvate oxidation by T cell precursors is necessary for optimal αβ T cell development and that its deficiency results in reduced but activated peripheral T cell populations. : Ramstead et al. show that mitochondrial pyruvate carrier 1, which mediates mitochondrial uptake of pyruvate, is necessary for proper development of αβ T cells. Consequently, deletion of MPC1 in early thymic development results in reduced numbers and abnormal activation of peripheral αβ T cells.
