Cell Division Is Not a “Clock” Measuring Acquisition of Competence to Produce IFN-γ or IL-4

Ben-Sasson, Shlomo Z.; Gerstel, Regina; Hu‐Li, Jane; Paul, William E.

doi:10.4049/jimmunol.166.1.112

Cited by 68 publications

(52 citation statements)

References 30 publications

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“…Only the cells that had divided were cytolytic, but the non-divided BM3.3 CD8 T cells activated by the pBM8/K bm8 complex were not anergized, as they (1) produced IFN-c and expressed CD44 in the primary response and (2) developed a very efficient recall response encompassing a complete functional program. Production of IFN-c in a manner independent of cell division has also been reported for naive CD4 T cells [21]. Therefore, the thresholds for induction of various effector functions and for T cell proliferation are distinct, as acquisition of cytotoxicity and cytokine secretion were strictly dependent on and independent of proliferation, respectively, in agreement with previous reports [22].…”

Section: Hierarchy Of a Cd8 T Cell Functional Program Dependent On Acsupporting

confidence: 89%

Temporal cross‐talk between TCR and STAT signals for CD8 T cell effector differentiation

et al. 2006

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The strength and duration of signaling through surface receptors is a primary means of controlling cell fate decisions. In adaptive immunity, Ag‐initiated T cell stimulation is secondarily regulated by cytokines. We here summarize evidence for temporal control of a gene expression program in naive CD8 T cells. It is initiated in response to TCR engagement but relies on secondary signaling from cytokine receptors to be sustained and to allow development of full effector capacity. This mechanism permits cytokine receptor signaling to rescue abortive TCR signaling, such as that induced in response to weak or partial TCR agonists. Indeed, limiting TCR‐initiated signaling on the Ras/ERK pathway may be complemented by STAT activation. Thus, TCR‐ and cytokine‐driven activation of transcription factors and epigenetic modifications may act in concert in a temporally staggered process to establish the functional program of effector CD8 T cells. Based on gene expression profiling, molecular targets whose activation or inactivation may boost or dampen CD8 T cell effectors are also identified. Manipulation of these targets may, respectively, increase anti‐tumor responses or prevent graft‐versus‐host reactions.

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Section: Hierarchy Of a Cd8 T Cell Functional Program Dependent On Acsupporting

confidence: 89%

Temporal cross‐talk between TCR and STAT signals for CD8 T cell effector differentiation

et al. 2006

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“…The more rapid expression of these proteins results from epigenetic modification such as DNA demethylation and chromatin remodeling. Although progression through the cell cycle can provide a window of opportunity to remodel chromatin and gene expression profiles to create new cellular phenotypes (1,40,41), the existence of a mechanistical link between cell division and the acquisition of cytokine synthesis capacity is still a matter of debate (42,43).…”

Section: Discussionmentioning

confidence: 99%

Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells

Quéméneur

Beloeil

Michallet

et al. 2004

The Journal of Immunology

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Nucleotide synthesis inhibitors are currently used in neoplastic diseases or as immunosuppressive agents for the prevention of acute rejection in organ transplantation and the treatment of autoimmune disorders. We have previously described that these inhibitors interfere with proliferation and survival of primary T cells in vitro. However, the precise effects of nucleotide restriction on effector and memory functions have not been elucidated. In this study, we investigated the impact of nucleotide synthesis inhibition on CD8 T cell differentiation by using TCR transgenic mice (F5) specific for the influenza virus nucleoprotein 68 peptide presented on the H-2Db molecule. Our results show that methotrexate and 5-fluorouracil prevent the acquisition of effector functions, such as IFN-γ, granzyme B expression, and cytotoxic function following antigenic stimulation of naive cells. Surprisingly, in the presence of mycophenolate mofetil, activated F5 cells are still able to produce granzyme B and to kill target cells but to a lesser extent compared with control. All three inhibitors interfere with the differentiation of naive cells into memory CD8 T cells. In contrast, the drugs are unable to inhibit the development of improved cytotoxic functions displayed by memory CD8 T cells.

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“…Furthermore, the data provide a possible mechanistic insight into this process. Thus, although Th 1 /Th 2 development is primarily driven by cytokines (such as IL-12 and IL-4), priming conditions such as the strength of antigenic stimulation play an important role in the decision (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Serial Triggering of T Cell Receptors Results in Incremental Accumulation of Signaling Intermediates

Borovsky¹,

Mishan-Eisenberg²,

Yaniv³

et al. 2002

Journal of Biological Chemistry

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Triggering of the T cell receptor (TCR) leads to the production of intracellular intermediates with half-life of a few minutes. Signaling kinetics of events originating from serial TCR triggering and its relation to antigen dose was investigated. In this study we documented incremental accumulation of short-lived intermediates of the extracellular signal-regulated kinase (ERK) family, produced during successive TCR triggering. The rate and extent of the intermediate accumulation are essentially determined by the level of TCR engagement and are augmented by costimulation. ERK-1 and ERK-2 exhibit different rates of accumulation following serial receptor triggering. The data indicate that the quantitative kinetic differences in downstream signaling pathways induce qualitatively distinct biological outcomes. Although CD69, interleukin-2, and interferon-␥ (IFN-␥) were primarily produced by high antigen doses that supported high MAPK phosphorylation, maximal interleukin-5 expression is induced by low and intermediate stimulus doses that do not support significant accumulation of activated ERK. We further demonstrated that the rate of phosphorylated ERK accumulation correlates with the duration of delay between T cell stimulation and the onset of IFN-␥ response, with stronger stimuli giving a more rapid IFN-␥ response. This delay might reflect the time required for the accumulation of signaling intermediates up to a threshold level that is necessary for activation. Thus, the data suggest that signaling events originating from serially triggered TCR are not simply sustained but are gradually accumulated and are integrated in a corresponding response.A single peptide antigen-major histocompatibility complex (MHC) 1 complex on the surface of an antigen-presenting cell (APC) can serially engage and trigger up to ϳ200 T cell receptors (TCRs) on a responding T cell (1). As a consequence of this "antigenic efficiency," relatively small numbers of peptide-MHC complexes on APC surfaces can trigger the threshold numbers of TCRs that are required for T cell activation (2).This intriguing feature of the T cell activation process makes physiological sense, in face of the antigenic complexity, as well as the consequent low frequency of any particular antigen, on the surface of any given APC in vivo.Any explanation of how serially receptor triggering leads to T cell activation must reconcile two opposing kinetic features. On the one hand, the signal emanating from each triggered TCR is short-lived and, in the absence of a continuous TCR triggering, the signal will stop. This point has been established by the demonstration that interference with continuous TCR engagement by peptide-MHC complexes can terminate signaling within minutes (3, 4). Furthermore, productive TCR engagement results in rapid TCR internalization and degradation (reviewed in Ref. 5). However, on the other hand, prolonged intracellular signaling over several hours is required for T cell activation (6).The intracellular signaling events underlying the serial trigge...

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Cell Division Is Not a “Clock” Measuring Acquisition of Competence to Produce IFN-γ or IL-4

Cited by 68 publications

References 30 publications

Temporal cross‐talk between TCR and STAT signals for CD8 T cell effector differentiation

Temporal cross‐talk between TCR and STAT signals for CD8 T cell effector differentiation

Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells

Serial Triggering of T Cell Receptors Results in Incremental Accumulation of Signaling Intermediates

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