TY - JOUR
T1 - Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells
AU - Lam, Wing Y.
AU - Becker, Amy M.
AU - Kennerly, Krista M.
AU - Wong, Rachel
AU - Curtis, Jonathan D.
AU - Llufrio, Elizabeth M.
AU - McCommis, Kyle S.
AU - Fahrmann, Johannes
AU - Pizzato, Hannah A.
AU - Nunley, Ryan M.
AU - Lee, Jieun
AU - Wolfgang, Michael J.
AU - Patti, Gary J.
AU - Finck, Brian N.
AU - Pearce, Erika L.
AU - Bhattacharya, Deepta
N1 - Funding Information:
This work was supported by NIH grants R01AI099108 (D.B.), R01AI091965 (E.L.P.), R01DK104735 (B.N.F.), R42AA021228 (B.N.F.), R01NS072241 (M.J.W.), and K01DK099395 (A.M.B.). This work was also supported by the New York Stem Cell Foundation and a Research Scholar grant from the American Cancer Society (125091-RSG-13-252-01-LIB, to D.B.). D.B. is a New York Stem Cell Foundation-Robertson Investigator. K.S.M. is a Diabetes Research Postdoctoral Training Program fellow (T32 DK07296 and DK007120). R.W. is supported by a predoctoral fellowship from the National Science Foundation (DGE-1143954). The West Coast Metabolomics Center is supported by NIH grant U24 DK-097154. RNA-seq analysis was performed by the Genome Technology Access Center at Washington University, supported by NIH grants P30CA91842 (Siteman Cancer Center) and UL1TR000448 (ICTS/CTSA). G.J.P. is a scientific advisory board member for Cambridge Isotope Laboratories. R.M.N. is a paid consultant for Biocomposites, Cardinal Health; CardioMEMS; DePUy, A Johnson & Johnson Company; Integra Sciences; Medtronic; Smith & Nephew; and Wright Medical Technology, Inc.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/7/19
Y1 - 2016/7/19
N2 - Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.
AB - Durable antibody production after vaccination or infection is mediated by long-lived plasma cells (LLPCs). Pathways that specifically allow LLPCs to persist remain unknown. Through bioenergetic profiling, we found that human and mouse LLPCs could robustly engage pyruvate-dependent respiration, whereas their short-lived counterparts could not. LLPCs took up more glucose than did short-lived plasma cells (SLPCs) in vivo, and this glucose was essential for the generation of pyruvate. Glucose was primarily used to glycosylate antibodies, but glycolysis could be promoted by stimuli such as low ATP levels and the resultant pyruvate used for respiration by LLPCs. Deletion of Mpc2, which encodes an essential component of the mitochondrial pyruvate carrier, led to a progressive loss of LLPCs and of vaccine-specific antibodies in vivo. Thus, glucose uptake and mitochondrial pyruvate import prevent bioenergetic crises and allow LLPCs to persist. Immunizations that maximize these plasma cell metabolic properties might thus provide enduring antibody-mediated immunity.
UR - http://www.scopus.com/inward/record.url?scp=84990852810&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2016.06.011
DO - 10.1016/j.immuni.2016.06.011
M3 - Article
C2 - 27396958
AN - SCOPUS:84990852810
VL - 45
SP - 60
EP - 73
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 1
ER -