scholarly journals Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation

2014 ◽  
Vol 211 (2) ◽  
pp. 345-356 ◽  
Author(s):  
Erin R. Mehlhop-Williams ◽  
Michael J. Bevan
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Protein Tyrosine Phosphatases ◽  
Central Memory ◽  
Naive T Cells ◽  
Memory Cd8 T Cells ◽  
Naïve T Cells

A hallmark of immunological memory is the ability of previously primed T cells to undergo rapid recall responses upon antigen reencounter. Classic work has suggested that memory T cells proliferate in response to lower doses of antigen than naive T cells and with reduced requirements for co-stimulation. In contrast to this premise, we observed that naive but not memory T cells proliferate in vivo in response to limited antigen presentation. To reconcile these observations, we tested the antigen threshold requirement for cell cycle entry in naive and central memory CD8+ T cells. Although both naive and memory T cells detect low dose antigen, only naive T cells activate cell cycle effectors. Direct comparison of TCR signaling on a single cell basis indicated that central memory T cells do not activate Zap70, induce cMyc expression, or degrade p27 in response to antigen levels that activate these functions in naive T cells. The reduced sensitivity of memory T cells may result from both decreased surface TCR expression and increased expression of protein tyrosine phosphatases as compared with naive T cells. Our data describe a novel aspect of memory T cell antigen threshold sensitivity that may critically regulate recall expansion.

scholarly journals Cell Cycle Entry Control in Naïve and Memory CD8+ T Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
David A. Lewis ◽  
Tony Ly
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Antigen Recognition ◽  
Cellular Growth ◽  
Activated T Cells ◽  
Memory Cd8 T Cells ◽  
Cell Cycle Entry

CD8+ T cells play important roles in immunity and immuno-oncology. Upon antigen recognition and co-stimulation, naïve CD8+ T cells escape from dormancy to engage in a complex programme of cellular growth, cell cycle entry and differentiation, resulting in rapid proliferation cycles that has the net effect of producing clonally expanded, antigen-specific cytotoxic T lymphocytes (CTLs). A fraction of activated T cells will re-enter dormancy by differentiating into memory T cells, which have essential roles in adaptive immunity. In this review, we discuss the current understanding of cell cycle entry control in CD8+ T cells and crosstalk between these mechanisms and pathways regulating immunological phenotypes.

scholarly journals Induction of memory-like CD8 + T cells and CD4 + T cells from human naïve T cells in culture

2021 ◽  
Author(s):  
Yasuhito Tokumoto ◽  
Yasuto Araki ◽  
Yusuke Narizuka ◽  
Yosuke Mizuno ◽  
Susumu Ohshima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Quiescent State ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Cells In Culture ◽  
Human T Cells

Abstract Memory T cells are crucial players in vertebrate adaptive immunity but their development is incompletely understood. Here we describe a method to produce human memory-like T cells from naïve human T cells in culture. Using commercially available human T cell differentiation kits, both purified naïve CD8 + T cells and purified naïve CD4 + T cells were activated via T cell receptor signaling and appropriate cytokines for several days in culture. All the T cell activators were then removed from the medium and the cultures were continued in hypoxic condition (1% O2 atmosphere) for several more days; during this period, most of the cells died, but some survived in a quiescent state for a month. The survivors had small round cell bodies, expressed differentiation markers characteristic of memory T cells and restarted proliferation when the T cell activators were added back. We could also induce memory-like T cells from naïve human T cells without hypoxia, if we froze the activated T cells or prepared the naïve T cells from chilled filter buffy coats.

A Comparison of Human CMVpp65-Specific Central Memory and Effector Memory CD8 T-Cells When Stimulated in-Vivo with IL-2 or IL-15/IL-15Rα Complex in a Murine Xenograft Model of Adoptive Cell Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4805-4805
Author(s):  
Tzu-Yun Kuo ◽  
Aisha Hasan ◽  
Richard J O'Reilly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Immunotherapy ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Central Memory ◽  
Effector Memory ◽  
Cell Clones

Abstract Initial clinical trials of adoptive immunotherapy have shown that the efficacy of adoptively transferred T-cells in man is often limited by the failure of cultured T cells, particularly cloned CD8 T cells, to persist in vivo. These studies demonstrated that the transferred T cells induced only transient responses and that persistence of the transferred T-cell clonotypes correlated with disease regression. A previous study suggested that CMV virus-specific CD8 T cell clones derived from central memory T cells (TCM), but not effector memory T cells (TEM), persisted long-term in non-human primates. On the other hand, another study comparing TCM and TEM derived SIV virus specific CD8 T-cell clones that were adoptively transferred in non-human primates demonstrated limited persistence of both TCM and TEM derived transferred T cells, and failed to show any difference between the two cell types. Because of these conflicting data, we have reexamed the persistence of adoptively transferred viral antigen specific T-cells derived from TCM and TEM population. Accordingly, we developed a NOG mouse model for studying the ability of human CMVpp65-specific T cells derived from central memory and effector memory populations to migrate to and accumulate in human tumor xenografts expressing CMVpp65, to alter the growth of these tumors and to persist in the tumors. This model also allows us to test immunomodulating agents and their ability to enhance targeted T-cell accumulations, antitumor activity and persistence. We analyzed CMVpp65-specific CD8 T cells derived from TCM and TEM precursors in vitro and in vivo. To tract the T-cells in vivo, we transduced membrane-bound Gaussia luciferase into TCM and TEM populations and monitored T cell trafficking by in vivo bioluminescence. Contrary to expectation, our results initially showed no differences between TCM and TEM derived CMVpp65-specific T-cell in mice co-treated with IL-2 in the time to accumulation, ultimate level of accumulation, degree of CMVpp65+ tumor regression or T-cell persistence. However, in mice cotreated with IL-15/IL-15Rα complex, both TCM and TEM exhibited more sustained engraftment and more prolonged accumulation in both the targeted tumor and in the marrow. In mice treated with IL-15/IL-15Rα, TCM and TEM derived T cells showed a similar effector memory phenotype and a similar level of regression of tumor growth. Thus, adoptive transfer of CMVpp65 specific TCM or TEM when combined with IL-15/IL-15Rα complex may support better persistence of antigen-specific T-cells following adoptive immunotherapy. Studies comparing IL-15/IL-15Rα complex with IL-15 alone are in progress. Disclosures No relevant conflicts of interest to declare.

The Cyclin-Dependent Kinase Inhibitor p27KIP1 Is Mandatory for Tolerance Induction In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 769-769
Author(s):  
Lequn Li ◽  
Alla Berezovskaya ◽  
Vassiliki A. Boussiotis
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
Treatment Group ◽  
Tolerance Induction ◽  
Binding Domain ◽  
Cyclin Dependent Kinase ◽  
Naive T Cells ◽  
Naïve T Cells

Abstract Elucidating the signals that influence the choice between T cell activation and tolerance in vivo will facilitate the design of novel therapies for the induction of transplantation tolerance. The cyclin-dependent kinase (cdk) inhibitor p27 is an important negative regulator of cell cycle progression in T lymphocytes. We have previously observed that in vitro generated anergic T cells express high levels of p27 and that forced expression of p27 renders T cells incapable of progressing through the cell cycle and transcribing the IL-2 gene. Therefore, we sought to determine the role of p27 on the decision of naive T cells between activation and tolerance in vivo. In order to eliminate the ability of p27 to regulate the cell cycle without disrupting other interactions of the protein, we used mice in which only the cdk-binding domain of p27 has been deleted resulting in a truncated form of p27 (p27tr). To generate a T cell population, which uniformly expresses a specific TCR that allows antigen-specific stimulation in vivo, we bred the DO11.10 TCR transgene onto the p27tr background. DO11.10 mice express a MHC class II-restricted transgenenic (Tg) TCR specific for OVA323–339 peptide that can be detected by a clonotypic antibody. To generate animals with T cells exclusively expressing the DO11.10 TCR, we crossed the DO11.10 TCR-Tg mice onto RAG2−/− background which eliminates endogenous TCRs. Naive T cells from DO11.10+RAG2−/−p27tr mice (termed p27tr/Tg) expressed markers identical to those of naive T cells from wild type DO11.10+RAG2−/− (termed WT-Tg) mice, allowing the accurate comparison of naive cells that differ only in their ability to express the p27 cdk-binding domain. Tg T cells from WT-Tg or p27tr/Tg mice were adoptively transferred into syngeneic recipients, which were injected with OVA323–339 either subcutaneously (primed) or intravenously (tolerized) according to established protocol. Draining lymph nodes were harvested and Tg cells were stimulated with OVA323–339 to determine their ability to respond on antigen-specific rechallenge. WT-Tg and p27tr/Tg cells from the primed treatment group had robust proliferation and production of IL-2. Strikingly, in the tolerant treatment group, although WT-Tg cells proliferated poorly and had significantly reduced IL-2 production, p27tr/Tg cells had proliferation and IL-2 production that were indistinguishable from the p27tr/Tg primed treatment group. Next we used blockade of costimulation to induce tolerance in vivo. Tg T cells from WT-Tg or p27tr/Tg mice were adoptively transferred into syngeneic recipients, which were treated with either PBS (primed) or with anti-CD40L mAb plus CTLA4-Ig (tolerized) and were immunized with OVA323–339 subcutaneously. Subsequent rechallenge with OVA323–339 revealed that, after in vivo treatment of anti-CD40L mAb and CTLA4-Ig, only WT-Tg cells became tolerant and were incapable of proliferating and producing IL-2, whereas responses of p27tr/Tg cells were not suppressed. Detailed analysis revealed that the failure of p27tr/Tg cells to undergo tolerance induction in the syngeneic recipients was not due to defective suppression by Treg, but due to the intrinsic inability of p27tr/Tg T cells to undergo arrest at the G1 phase of the cell cycle during tolerogenic treatment. These results demonstrate a key role for p27 in determining the outcome of naive T cell encounter with a tolerogenic stimulus in vivo and have significant implications for developing of immune based therapies geared towards tolerance induction.

scholarly journals Cytokine-driven Proliferation and Differentiation of Human Naive, Central Memory, and Effector Memory CD4+ T Cells

2001 ◽  
Vol 194 (12) ◽  
pp. 1711-1720 ◽  
Author(s):  
Jens Geginat ◽  
Federica Sallusto ◽  
Antonio Lanzavecchia
Keyword(s):  
T Cells ◽  
Map Kinases ◽  
High Efficiency ◽  
Memory T Cells ◽  
Effector Function ◽  
Central Memory ◽  
Receptor Expression ◽  
Effector Memory ◽  
Naive T Cells ◽  
Naïve T Cells

Memory T lymphocytes proliferate in vivo in the absence of antigen maintaining a pool of central memory T cells (TCM) and effector memory T cells (TEM) with distinct effector function and homing capacity. We compared human CD4+ naive T, TCM, and TEM cells for their capacity to proliferate in response to cytokines, that have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency TEM, while TCM were less responsive and naive T cells failed to respond. Dendritic cells (DCs) and DC-derived cytokines allowed naive T cells to proliferate selectively in response to IL-4, and potently boosted the response of TCM to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rβ and the common γ chain (γc). The extracellular signal regulated kinase and the p38 mitogen-activated protein (MAP) kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures, some of the proliferating TCM differentiated to TEM-like cells acquiring effector function and switching chemokine receptor expression from CCR7 to CCR5. The sustained antigen-independent generation of TEM from a pool of TCM cells provides a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4+ memory T cells.

scholarly journals CXCL12 Mediates CCR7-independent Homing of Central Memory Cells, But Not Naive T Cells, in Peripheral Lymph Nodes

2004 ◽  
Vol 199 (8) ◽  
pp. 1113-1120 ◽  
Author(s):  
M. Lucila Scimone ◽  
Thomas W. Felbinger ◽  
Irina B. Mazo ◽  
Jens V. Stein ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Cd8 T Cells ◽  
Lymphoid Organs ◽  
Central Memory ◽  
T Cell Subsets ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Peripheral Lymph ◽  
Secondary Lymphoid Organs

Central memory CD8+ T cells (TCM) confer superior protective immunity against infections compared with other T cell subsets. TCM recirculate mainly through secondary lymphoid organs, including peripheral lymph nodes (PLNs). Here, we report that TCM, unlike naive T cells, can home to PLNs in both a CCR7-dependent and -independent manner. Homing experiments in paucity of lymph node T cells (plt/plt) mice, which do not express CCR7 ligands in secondary lymphoid organs, revealed that TCM migrate to PLNs at ∼20% of wild-type (WT) levels, whereas homing of naive T cells was reduced by 95%. Accordingly, a large fraction of endogenous CD8+ T cells in plt/plt PLNs displayed a TCM phenotype. Intravital microscopy of plt/plt subiliac lymph nodes showed that TCM rolled and firmly adhered (sticking) in high endothelial venules (HEVs), whereas naive T cells were incapable of sticking. Sticking of TCM in plt/plt HEVs was pertussis toxin sensitive and was blocked by anti-CXCL12 (SDF-1α). Anti-CXCL12 also reduced homing of TCM to PLNs in WT animals by 20%, indicating a nonredundant role for this chemokine in the presence of physiologic CCR7 agonists. Together, these data distinguish naive T cells from TCM, whereby only the latter display greater migratory flexibility by virtue of their increased responsiveness to both CCR7 ligands and CXCL12 during homing to PLN.

scholarly journals Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1916-1923 ◽  
Author(s):  
Nia Tatsis ◽  
Julie C. Fitzgerald ◽  
Arturo Reyes-Sandoval ◽  
Kimberly C. Harris-McCoy ◽  
Scott E. Hensley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adenovirus Vector ◽  
Adenoviral Vectors ◽  
Central Memory ◽  
Activated T Cells ◽  
Memory Cd8 T Cells ◽  
Central Memory Cells

AbstractCD8+ T cell-numbers rapidly expand and then contract after exposure to their cognate antigen. Here we show that the sustained frequencies of transgene product-specific CD8+ T cells elicited by replication-defective adenovirus vectors are linked to persistence of low levels of transcriptionally active adenovirus vector genomes at the site of inoculation, in liver, and lymphatic tissues. Continuously produced small amounts of antigen maintain fully active effector CD8+ T cells, while also allowing for their differentiation into central memory cells. The long-term persistence of adenoviral vectors may be highly advantageous for their use as vaccines against pathogens for which T-cell–mediated protection requires both fully activated T cells for immediate control of virus-infected cells and central memory CD8+ T cells that, because of their higher proliferative capacity, may be suited best to eliminate cells infected by pathogens that escaped the initial wave of effector T cells.

scholarly journals Strong homeostatic TCR signals induce formation of self-tolerant virtual memory CD8 T cells

2017 ◽  
Author(s):  
Ales Drobek ◽  
Alena Moudra ◽  
Daniel Mueller ◽  
Martina Huranova ◽  
Veronika Horkova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Fate ◽  
Memory T Cells ◽  
Autoimmune Diabetes ◽  
Virtual Memory ◽  
Naive T Cells ◽  
Memory Cd8 T Cells ◽  
Foreign Antigen ◽  
Naïve T Cells

AbstractVirtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute for 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing TCR repertoires and using retrogenic monoclonal T-cell populations, we show that virtual memory T cells originate exclusively from strongly self-reactive T cells. Moreover, we show that the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T-cell clones. We propose a so far unappreciated peripheral T-cell fate decision checkpoint that eventually leads to the differentiation of highly self-reactive T cells into virtual memory T cells. This underlines the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they do not show higher capacity to induce autoimmune diabetes than naïve T cells. Thus, virtual memory T cells are not generally more responsive than naïve T cells, because their activity highly depends on the immunological context.SummaryWe conclude that virtual memory T cells are formed from self-reactive CD8+ T cells in a process regulated by CD8-Lck stoichiometry. Despite their self-reactivity and partial memory differentiation program, virtual memory T cells did not show a strong autoimmune potential.

scholarly journals Developmental Regulation of Lck Targeting to the CD8 Coreceptor Controls Signaling in Naive and Memory T Cells

1999 ◽  
Vol 189 (10) ◽  
pp. 1521-1530 ◽  
Author(s):  
Martin F. Bachmann ◽  
Awen Gallimore ◽  
Susanne Linkert ◽  
Vincenzo Cerundolo ◽  
Antonio Lanzavecchia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Developmental Regulation ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Naive T Cells ◽  
Naïve T Cells

The question of whether enhanced memory T cell responses are simply due to an increased frequency of specific cells or also to an improved response at the single cell level is widely debated. In this study, we analyzed T cell receptor (TCR) transgenic memory T cells and bona fide memory T cells isolated from virally infected normal mice using the tetramer technology. We found that memory T cells are qualitatively different from naive T cells due to a developmentally regulated rearrangement of the topology of the signaling machinery. In naive cytotoxic T cells, only a few CD8 molecules are associated with Lck and the kinase is homogeneously distributed inside the cell. However, in vivo priming of naive T cells induces the targeting of Lck to the CD8 coreceptor in the cell membrane and the consequent organization of a more efficient TCR signaling machinery in effector and memory cells.

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