Mitochondrial Priming by CD28

Abstract

SUMMARY 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 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 essential for future T cell responses.

Fatty acid metabolism in CD8+ T cell memory: Challenging current concepts

“…Several studies have attempted to describe unique metabolic conditions that favour the development of long-lasting adaptive memory, as this information could be crucial to improve the effectiveness of vaccination or cancer treatment (176). Taken together, some of these studies had ultimately proposed that CD8 + T mem cells present an exceptional requirement for mitochondrial oxidation of fatty acids to sustain their survival and secondary activation, and identified an important role for CPT1A, an enzyme that can control the rate of LC-FAO, in modulating this adaptation (70, 71, 106, 131). Due to the absence of sufficient in vivo data and specific genetic models to evaluate this hypothesis, the current paradigm was based on the use of a chemical inhibitor of CPT1, etomoxir, and the analysis of in vitro cultures with IL-15 of antigen-stimulated CD8 + T cells.…”

“…Interestingly, 4–1BB-expressing cells were also characterized by enhanced mitochondrial biogenesis and metabolism, higher SRC and rates of FAO, as well as a differential expression of metabolic genes favouring FA metabolism over glycolysis, including Cpt1a and Fabp5 (191). Signalling through CD28 intracellular domain was also described to increase Cpt1a expression when compared to T cells harbouring only the transgenic antigen-specific receptor (131). …”

Chimeric antigen receptor T cell persistence and memory cell formation

“…This was first demonstrated by pioneering studies showing that inhibition of the mammalian target of rapamycin (mTOR) pathway and enhancement of fatty acid oxidation induced an increase in the differentiation rate of memory CD8 + T cells . The production of metabolically “fit” memory cells appears to be promoted by mitochondrial remodeling, including networks of fused mitochondria, with recent findings showing that CD28 co‐stimulation drives that process . T CM either synthesize their own fatty acids in order to drive fatty acid oxidation, or in the case of skin T RM , use the more direct pathway of free fatty acid uptake (involving the fatty acid‐binding proteins Fabp4 and Fabp5) to satisfy their fatty acid oxidation needs .…”

The metabolic spectrum of memory T cells

“…A number of mitochondrial pathways are engaged or remodeled early after activation, including mitochondrial ROS to augment nuclear factor of activated T cells activation and one carbon metabolism to support purine and thymidine synthesis . Costimulation can contribute to enhanced mitochondrial respiratory functions early after activation . Thus, while upregulation of aerobic glycolysis is important for effector T‐cell development and function, mitochondrial metabolism also has a prominent role.…”