scholarly journals Autophagy is a critical regulator of memory CD8+ T cell formation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Daniel J Puleston ◽  
Hanlin Zhang ◽  
Timothy J Powell ◽  
Elina Lipina ◽  
Stuart Sims ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Bulk Material ◽  
Cd8 T Cell ◽  
Memory Formation ◽  
T Cell Memory ◽  
Dependent Manner ◽  
Cell Memory ◽  
Cd8 T Cell Memory

During infection, CD8+ T cells initially expand then contract, leaving a small memory pool providing long lasting immunity. While it has been described that CD8+ T cell memory formation becomes defective in old age, the cellular mechanism is largely unknown. Autophagy is a major cellular lysosomal degradation pathway of bulk material, and levels are known to fall with age. In this study, we describe a novel role for autophagy in CD8+ T cell memory formation. Mice lacking the autophagy gene Atg7 in T cells failed to establish CD8+ T cell memory to influenza and MCMV infection. Interestingly, autophagy levels were diminished in CD8+ T cells from aged mice. We could rejuvenate CD8+ T cell responses in elderly mice in an autophagy dependent manner using the compound spermidine. This study reveals a cell intrinsic explanation for poor CD8+ T cell memory in the elderly and potentially offers novel immune modulators to improve aged immunity.

scholarly journals N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation

2013 ◽  
Vol 210 (7) ◽  
pp. 1463-1479 ◽  
Author(s):  
Salvador Iborra ◽  
Manuel Ramos ◽  
David M. Arana ◽  
Silvia Lázaro ◽  
Francisco Aguilar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Small Gtpase ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cd8 T Cell Memory

Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate.

scholarly journals NKG2D signaling on CD8+ T cells represses T-bet and rescues CD4-unhelped CD8+ T cell memory recall but not effector responses

2012 ◽  
Vol 18 (3) ◽  
pp. 422-428 ◽  
Author(s):  
Andrew Zloza ◽  
Frederick J Kohlhapp ◽  
Gretchen E Lyons ◽  
Jason M Schenkel ◽  
Tamson V Moore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Memory Recall ◽  
Cell Memory ◽  
Cd8 T Cell Memory

scholarly journals Mammalian Target of Rapamycin Complex 2 Controls CD8 T Cell Memory Differentiation in a Foxo1-Dependent Manner

Cell Reports ◽  
2016 ◽  
Vol 14 (5) ◽  
pp. 1206-1217 ◽  
Author(s):  
Lianjun Zhang ◽  
Benjamin O. Tschumi ◽  
Isabel C. Lopez-Mejia ◽  
Susanne G. Oberle ◽  
Marten Meyer ◽  
...  
Keyword(s):  
T Cell ◽  
Mammalian Target Of Rapamycin ◽  
Cd8 T Cell ◽  
Target Of Rapamycin ◽  
T Cell Memory ◽  
Dependent Manner ◽  
Cell Memory ◽  
Memory Differentiation ◽  
Cd8 T Cell Memory

scholarly journals Regulation of Memory CD8 T-Cell Differentiation by Cyclin-Dependent Kinase Inhibitor p27Kip1

2010 ◽  
Vol 30 (21) ◽  
pp. 5145-5159 ◽  
Author(s):  
Anju Singh ◽  
Anna Jatzek ◽  
Erin Hemmila Plisch ◽  
Rajini Srinivasan ◽  
John Svaren ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Kinase Inhibitor ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Cell Memory ◽  
Memory Cd8 T Cells ◽  
Cyclin Dependent Kinase Inhibitor

ABSTRACT Induction of potent T-cell memory is the goal of vaccinations, but the molecular mechanisms that regulate the formation of memory CD8 T cells are not well understood. Despite the recognition that controls of cellular proliferation and apoptosis govern the number of memory T cells, the cell cycle regulatory mechanisms that control these key cellular processes in CD8 T cells during an immune response are poorly defined. Here, we have identified the cyclin-dependent kinase inhibitor p27Kip1 as a critical regulator of the CD8 T-cell homeostasis at all phases of the T-cell response to an acute viral infection in mice. By acting as a timer for cell cycle exit, p27Kip1 curtailed the programmed expansion of interleukin-2-producing memory precursors and markedly limited the magnitude and quality of CD8 T-cell memory. In the absence of p27Kip1, CD8 T cells showed superior recall responses shortly after vaccination with recombinant Listeria monocytogenes. Additionally, we show that p27Kip1 constrains proliferative renewal of memory CD8 T cells, especially of the effector memory subset. These findings provide critical insights into the cell cycle regulation of CD8 T-cell homeostasis and suggest that modulation of p27Kip1 could bolster vaccine-induced T-cell memory and protective immunity.

scholarly journals Cholesterol-lowering Decreased mTOR Complex 2 Signaling and Enhanced Antitumor Immunity

2021 ◽  
Author(s):  
Yanping Wang ◽  
Sungyong You ◽  
Shengchen Su ◽  
Austin Yeon ◽  
Eric M. Lo ◽  
...  
Keyword(s):  
T Cell ◽  
Serum Cholesterol ◽  
Antitumor Immunity ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Lymphocyte Function ◽  
Dependent Manner ◽  
Cell Memory ◽  
Cholesterol Lowering ◽  
Cd8 T Cell Memory

SummaryCholesterol-lowering interventions are employed widely and safely to reduce risk of cardiovascular disease. Cholesterol may have complex and opposing effects on immunity. We lowered serum cholesterol to clinically relevant levels in mice and evaluated the final adaptive immune response. Mice treated with oral ezetimibe exhibited enhanced antitumor immunity against syngeneic cancers in a CD8+ lymphocyte-dependent manner, produced immunity that was transferrable through lymphocytes, and enhanced central CD8+ T cell memory. In both mice and patients undergoing prostatectomy, lowering serum cholesterol inhibited mTORC2 signaling in lymphocytes and increased infiltration of CD8+ lymphocytes into prostate tumors. Lymphocyte-specific mTORC2 knockout mice demonstrated enhanced CD8+ lymphocyte function and antitumor capacity. In a prospective clinical trial, cholesterol-lowering intervention prior to prostatectomy decreased the proliferation of normal prostate and low-grade adenocarcinomas. Here, we show that lowering serum cholesterol may be an effective strategy to decrease signaling through mTORC2 and enhance antitumor CD8+ T cell memory.

scholarly journals TNIK signaling imprints CD8+ T cell memory formation early after priming

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Carla A. Jaeger-Ruckstuhl ◽  
Magdalena Hinterbrandner ◽  
Sabine Höpner ◽  
Colin E. Correnti ◽  
Ursina Lüthi ◽  
...  
Keyword(s):  
T Cell ◽  
Cd8 T Cell ◽  
Memory Formation ◽  
T Cell Memory ◽  
Cell Memory ◽  
Cd8 T Cell Memory

scholarly journals OX40 Ligation of CD4+T Cells Enhances Virus-Specific CD8+T Cell Memory Responses Independently of IL-2 and CD4+T Regulatory Cell Inhibition

2006 ◽  
Vol 176 (4) ◽  
pp. 2486-2495 ◽  
Author(s):  
Qigui Yu ◽  
Feng Yun Yue ◽  
Xiao X. Gu ◽  
Herbert Schwartz ◽  
Colin M. Kovacs ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
T Regulatory Cell ◽  
Cell Memory ◽  
Regulatory Cell ◽  
Cd8 T Cell Memory ◽  
Cell Inhibition
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