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 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 Role of T cell receptor signaling in CD8 T cell memory

2015 ◽  
Author(s):  
◽  
Karin M. Knudson
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Immunological Memory ◽  
Cell Receptor ◽  
T Cell Memory ◽  
Cell Memory ◽  
Memory Cd8 T Cells ◽  
Memory Differentiation

The generation of immunological memory is the basis for vaccination. The development of memory CD8 T cells is required for long-term protection against intracellular pathogens, such as viruses, and tumors. While the importance of memory generation has been recognized for over 30 years, the mechanism by which memory CD8 T cells arise during immune responses is still not fully understood. T cell receptor (TCR) interaction with antigen (immunogenic peptide)-bound MHC is necessary for activation and differentiation of CD8 T cells. Yet, how the resulting TCR signal regulates T cell memory is unknown. In this dissertation, we investigated the role that the TCR signal plays in memory differentiation. First, we explain how the strength of pMHC-TCR interaction affects memory generation. We also demonstrate that the signals for the development of memory are different depending on TCR ligand strength. Finally, we define a mechanism by which TCR signaling programs memory differentiation. All vaccines utilize pathogen-specific antigens to induce immunological memory. By understanding how antigenic signals program memory differentiation, it will be possible to specifically manipulate this process. We can then produce more effective and longer lasting memory cells.

scholarly journals Combination Adjuvants Affect the Magnitude of Effector-Like Memory CD8 T Cells and Protection against Listeriosis

2021 ◽  
Author(s):  
Woojong Lee ◽  
Autumn Larsen ◽  
Brock Kingstad-Bakke ◽  
Chandranaik B. Marinaik ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Memory Cd8 T Cells ◽  
Cross Presentation ◽  
Nano Emulsion ◽  
Cd8 T Cell Memory

Development of T-cell-based subunit protein vaccines against diseases, such as tuberculosis and malaria, remains a challenge for immunologists. Here, we have identified a nano-emulsion adjuvant Adjuplex (ADJ), which enhanced dendritic cell (DC) cross-presentation and elicited effective memory T cell-based immunity to Listeria monocytogenes (LM). We further evaluated whether cross-presentation induced by ADJ, can be combined with the immunomodulatory effects of TLR agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke systemic CD8 T cell-based immunity to LM. Mechanistically, vaccination with ADJ, alone or in combination with CpG or GLA augmented activation and antigen uptake by CD103+ migratory and CD8α+ resident DCs and up-regulated CD69 expression on B and T lymphocytes in vaccine-draining lymph nodes. By engaging basic leucine zipper ATF-like transcription factor 3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided effective immunity to LM in spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in spleen, but not in the liver. Surprisingly, combining CpG or GLA with ADJ reduced the number of ADJ-induced memory CD8 T cells and compromised protective immunity to LM, especially in the liver. Taken together, data presented in this manuscript provides a glimpse of protective CD8 T cell memory differentiation induced by a nano-emulsion adjuvant and demonstrates the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to LM, a model intracellular pathogen.

scholarly journals Subunit Vaccine-Elicited Effector-Like Memory CD8 T Cells Protect Against Listeriosis

2020 ◽  
Author(s):  
Woojong Lee ◽  
Autumn Larsen ◽  
Brock Kingstad-Bakke ◽  
M. Suresh
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Cd8 T Cell ◽  
T Cell Memory ◽  
Memory Cd8 T Cells ◽  
Cell Immunity ◽  
Nano Emulsion ◽  
Cd8 T Cell Memory

AbstractDevelopment of T-cell-based subunit protein vaccines against diseases, such as AIDS, tuberculosis and malaria remains a challenge for immunologists. Here, we have evaluated whether cross-presentation induced by nanoemulsion adjuvant Adjuplex (ADJ), can be combined with the immunomodulatory effects of TLR agonists (CpG or glucopyranosyl lipid adjuvant [GLA]) to evoke protective systemic CD8 T cell-based immunity to Listeria monocytogenes (LM). Vaccination with ADJ, alone or in combination with CpG or GLA augmented activation and antigen uptake by migratory and resident dendritic cells and up-regulated CD69 expression on B and T lymphocytes in draining lymph nodes. By virtue of its ability to engage BATF3-dependent cross-presenting DCs, ADJ potently elicited effector CD8 T cells that differentiated into a distinct subset of granzyme B-expressing CD27LO effector-like memory CD8 T cells, which provided highly effective immunity to LM in spleen and liver. CpG or GLA alone did not elicit effector-like memory CD8 T cells and induced moderate protection in spleen, but not in the liver. Surprisingly, combining CpG or GLA with ADJ limited the magnitude of ADJ-induced CD8 T cell memory and compromised protective immunity to LM, especially in the liver. Taken together, data presented in this manuscript provides a glimpse of protective CD8 T cell memory differentiation induced by a nano-emulsion adjuvant and demonstrates the unexpected negative effects of TLR signaling on the magnitude of CD8 T cell memory and protective immunity to listeriosis.ImportanceTo date, the most effective vaccines primarily provide protection by eliciting neutralizing antibodies, while development of T-cell-based subunit vaccines against infectious diseases, such as tuberculosis and malaria, remains a challenge for immunologists. Axiomatically, engagement of multiple innate immune receptors early in the response might be key to programming effective immunity. Hence, there is an impetus to develop combination adjuvants that engage multiple innate signaling pathways and additionally promote cross-presentation to stimulate CD8 T-cell immunity. Here, we show that a nano-emulsion adjuvant ADJ alone elicits effector-like memory CD8 T cells and provides highly effective immunity to listeriosis; combining ADJ with TLR agonists, including CpG and GLA, compromised T cell immunity to LM. In summary, this study provided fundamental insights into the effects of combining innate immune signaling with nano-emulsion adjuvants on memory T cell differentiation and protective immunity. These findings are expected to have implications in the use of combination adjuvants to develop subunit vaccines that engender systemic CD8 T-cell immunity to intracellular pathogens.

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 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.

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