Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory Development

Windt, Gerritje J. W. van der; Everts, Bart; Chang, Chih‐Hao; Curtis, Jonathan D.; Freitas, Tori C.; Amiel, Eyal; Pearce, Edward J.; Pearce, Erika L.

doi:10.1016/j.immuni.2011.12.007

Cited by 1,261 publications

(1,415 citation statements)

References 49 publications

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“…Possibly it executes this role by bringing Dap10 into the IL-15 signaling complex, as was previously suggested (11). Interestingly, IL-15 was recently shown to mediate transition from glycolytic to oxidative metabolism during memory differentiation by inducing mitochondrial biogenesis (35). Thus, a model appears in which the NKG2D/IL-15R axis facilitates the transition from effector to memory stage.…”

Section: Discussionmentioning

confidence: 66%

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Wensveen

Lenartić

Jelenčić

et al. 2013

The Journal of Immunology

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Memory formation of activated CD8 T cells is the result of a specific combination of signals that promote long-term survival and inhibit differentiation into effector cells. Much is known about initial cues that drive memory formation, but it is poorly understood which signals are essential during the intermediate stages before terminal differentiation. NKG2D is an activating coreceptor on Ag-experienced CD8 T cells that promotes effector cell functions. Its role in memory formation is currently unknown. In this study, we show that NKG2D controls formation of CD8 memory T cells by promoting survival of precursor cells. We demonstrate that NKG2D enhances IL-15–mediated PI3K signaling of activated CD8 T cells, in a specific phase of memory cell commitment, after activation but before terminal differentiation. This signal is essential for the induction of prosurvival protein Mcl-1 and precursor cell survival. In vivo, NKG2D deficiency results in reduced memory cell formation and impaired protection against reinfection. Our findings show a new role for PI3K and the NKG2D/IL-15 axis in an underappreciated stage of effector to memory cell transition that is essential for the generation of antiviral immunity. Moreover, we provide novel insights how these receptors control both effector and memory T cell differentiation.

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Section: Discussionmentioning

confidence: 66%

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Wensveen

Lenartić

Jelenčić

et al. 2013

The Journal of Immunology

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“…Cytokines IL-2 and IL-15 are critical for the development and maintenance of CD8 + effector and memory T cells, respectively (36). To understand upstream and downstream mechanisms underlying Tsc1-dependent memory T-cell differentiation, we used an in vitro culture system that mimics the programs of effector and memory T-cell differentiation (13,37) and examined the effect of acute deletion of Tsc1 in this system. To this end, we crossed Tsc1 fl/fl with Rosa26-Cre-ER T2 (CreER) and OT-I transgenic mice.…”

Section: Resultsmentioning

confidence: 99%

“…Emerging studies indicate that distinct metabolic pathways contribute to the fate decisions of effector and memory T cells. For instance, the increased glycolytic metabolism promotes effector T-cell generation (11), whereas oxidative phosphorylation and mitochondrial spare respiratory capacity facilitate memory T-cell differentiation (12,13). Recent studies have also identified transcriptional regulators of cell metabolism that promote effector T-cell differentiation, including HIF1 and IRF4 (14)(15)(16)(17).…”

mentioning

confidence: 99%

Tsc1 promotes the differentiation of memory CD8 ⁺ T cells via orchestrating the transcriptional and metabolic programs

Shrestha

Yang²,

Wei³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Enhancing the generation and function of memory T cells represents a crucial strategy to improve protective immunity against pathogens and tumors. The signaling pathway via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells, but the upstream regulators or downstream mechanisms remain unclear. In this study, we provide insight into the mechanistic basis that controls mTOR signaling and memory T-cell responses. The deficiency of tuberous sclerosis 1 (Tsc1) in antigen-experienced T cells impairs the differentiation of memory T-cell precursors and the formation of memory T cells, associated with excessive mTOR activity and dysregulated cell metabolism. Our study establishes a molecular mechanism that links mTOR signaling and cell metabolism for memory T-cell development.

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“…6C), die because they cannot sustain their bioenergetic needs. Because memory T cells generally rely on oxidative phosphorylation for their bioenergetic requirements compared with effector cells, which primarily use glycolysis (45,46), a reduced mitochondrial mass and, thus, lower mitochondrial spare respiratory capacity in CD27-generated memory cells, could lead to their rapid demise.…”

Section: Discussionmentioning

confidence: 99%

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

Willoughby

Kerr

Rogel

et al. 2014

The Journal of Immunology

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The factors that determine differentiation of naive CD8 T cells into memory cells are not well understood. A greater understanding of how memory cells are generated will inform of ways to improve vaccination strategies. In this study, we analyzed the CD8 T cell response elicited by two experimental vaccines comprising a peptide/protein Ag and an agonist that delivers a costimulatory signal via CD27 or 4-1BB. Both agonists increased expansion of Ag-specific CD8 T cells compared with Ag alone. However, their capacity to stimulate differentiation into effector and memory cells differed. CD27 agonists promoted increased expression of perforin and the generation of short-lived memory cells, whereas stimulation with 4-1BB agonists favored generation of stable memory. The memory-promoting effects of 4-1BB were independent of CD4 T cells and were the result of programing within the first 2 d of priming. Consistent with this conclusion, CD27 and 4-1BB–stimulated CD8 T cells expressed disparate amounts of IL-2, IFN-γ, CD25, CD71, and Gp49b as early as 3 d after in vivo activation. In addition, memory CD8 T cells, generated through priming with CD27 agonists, proliferated more extensively than did 4-1BB–generated memory cells, but these cells failed to persist. These data demonstrate a previously unanticipated link between the rates of homeostatic proliferation and memory cell attrition. Our study highlights a role for these receptors in skewing CD8 T cell differentiation into effector and memory cells and provides an approach to optimize vaccines that elicit CD8 T cell responses.

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Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory Development

Cited by 1,261 publications

References 49 publications

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Tsc1 promotes the differentiation of memory CD8 ⁺ T cells via orchestrating the transcriptional and metabolic programs

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

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Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory Development

Cited by 1,261 publications

References 49 publications

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Tsc1 promotes the differentiation of memory CD8 + T cells via orchestrating the transcriptional and metabolic programs

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

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Tsc1 promotes the differentiation of memory CD8 ⁺ T cells via orchestrating the transcriptional and metabolic programs