TY - JOUR
T1 - Mitochondrial Priming by CD28
AU - Klein Geltink, Ramon I.
AU - O'Sullivan, David
AU - Corrado, Mauro
AU - Bremser, Anna
AU - Buck, Michael D.
AU - Buescher, Joerg M.
AU - Firat, Elke
AU - Zhu, Xuekai
AU - Niedermann, Gabriele
AU - Caputa, George
AU - Kelly, Beth
AU - Warthorst, Ursula
AU - Rensing-Ehl, Anne
AU - Kyle, Ryan L.
AU - Vandersarren, Lana
AU - Curtis, Jonathan D.
AU - Patterson, Annette E.
AU - Lawless, Simon
AU - Grzes, Katarzyna
AU - Qiu, Jing
AU - Sanin, David E.
AU - Kretz, Oliver
AU - Huber, Tobias B.
AU - Janssens, Sophie
AU - Lambrecht, Bart N.
AU - Rambold, Angelika S.
AU - Pearce, Edward J.
AU - Pearce, Erika L.
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/10/5
Y1 - 2017/10/5
N2 - T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation—cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses. Costimulatory signals during the initial phase of T cell activation prime mitochondria with latent metabolic capacity essential for future T cell responses.
AB - T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation—cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses. Costimulatory signals during the initial phase of T cell activation prime mitochondria with latent metabolic capacity essential for future T cell responses.
KW - CD28
KW - CD8 T cells
KW - Cpt1a
KW - adoptive cellular immunotherapy
KW - costimulation
KW - memory T cells
KW - mir33
KW - mitochondrial cristae remodeling
KW - mitochondrial morphology
KW - spare respiratory capacity
UR - http://www.scopus.com/inward/record.url?scp=85029443360&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85029443360&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2017.08.018
DO - 10.1016/j.cell.2017.08.018
M3 - Article
C2 - 28919076
AN - SCOPUS:85029443360
SN - 0092-8674
VL - 171
SP - 385-397.e11
JO - Cell
JF - Cell
IS - 2
ER -