CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death

Janssen, Edith M.; Droin, Nathalie; Lemmens, Edward E.; Pinkoski, Michael J.; Bensinger, Steven J.; Ehst, Benjamin D.; Griffith, Thomas S.; Green, Douglas R.; Schoenberger, Stephen P.

doi:10.1038/nature03337

Cited by 560 publications

(544 citation statements)

References 26 publications

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“…Thus, we conclude that apoptosis was induced in a paracrine manner by membrane-bound TRAIL. This result corresponds to previous publications characterizing the bystander effect of virally expressed TRAIL, 16 or describing that the production of relevant amounts of sTRAIL by mammalian cells involves secretion of sTRAIL from intracellular stores, 38,39 rather than shedding of the extracellular domain of TRAIL present on the plasma membrane. The analysis of TRAIL receptor expression revealed high surface levels of TRAIL-R2 and lower, but still readily detectable levels of TRAIL-R1, at all culture conditions tested.…”

Section: Discussionsupporting

confidence: 90%

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

Wenger

Mattern²,

Haas

et al. 2006

Cancer Gene Ther

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, which selectively induces apoptosis in many transformed cells without apparent toxic side effects in normal tissue. We recently described the construction and characterization of a lentiviral vector for expression of TRAIL. In this report, we evaluate its suitability for therapeutic application. In vitro, we observed specific induction of apoptosis upon transduction in human lung cancer cells. Cell death was partially dependent on successful integration and TRAIL expression by the vectors, but was to some extent mediated by protein carryover, as we found TRAIL protein associated with virus particles. Transduction of subcutaneously growing lung tumors on nude mice with lentiviral TRAIL mediated a transient suppression of tumor growth. Analysis of tumor sections revealed that transduction efficiency of lentiviral control vector but not of lentiviral TRAIL vector was high. This was because of the direct cytotoxic activity of recombinant TRAIL present in viral particles, which prevented efficient tumor transduction. These data therefore suggest that enveloped viral vectors constitutively expressing TRAIL are well suited for ex vivo applications, such as the transduction of tumorhoming cells, but may have a lower effect when used directly for the transduction of tumor cells in vivo.

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Section: Discussionsupporting

confidence: 90%

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

Wenger

Mattern²,

Haas

et al. 2006

Cancer Gene Ther

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“…Recently, Janssen et al [8] showed that CD8 + T cells that are primed in the absence of CD4 + T cell help commit activation-induced cell death when they reencounter antigen. They found that unlike helped CD8 + memory T cells, these helpless memory CTL synthesize TRAIL upon restimulation.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the production of acute effector cytokines and IL-2 are reduced [7]. "Unhelped" CD8 + T cells die upon in vitro re-activation, due to the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is not expressed by "helped" CD8 + memory T cells [8].…”

Section: Introductionmentioning

confidence: 99%

CD4⁺ T cell help improves CD8⁺ T cell memory by retained CD27 expression

2008

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CD4 + T cell help during the priming of CD8 + T lymphocytes imprints the capacity for optimal secondary expansion upon re-encounter with antigen. Helped memory CD8 + T cells rapidly expand in response to a secondary antigen exposure, even in the absence of T cell help and, are most efficient in protection against a re-infection. In contrast, helpless memory CTL can mediate effector function, but secondary expansion is reduced. How CD4 + T cells instruct CD8 + memory T cells during priming to undergo efficient secondary expansion has not been resolved in detail. Here, we show that memory CTL after infection with lymphocytic choriomeningitis virus are CD27 high whereas memory CTL primed in the absence of CD4 + T cell have a reduced expression of CD27. Helpless memory CTL produced low amounts of IL-2 and did not efficiently expand after restimulation with peptide in vitro. Blocking experiments with monoclonal antibodies and the use of CD27 -/-memory CTL revealed that CD27 ligation during restimulation increased autocrine IL-2 production and secondary expansion. Therefore, regulating CD27 expression on memory CTL is a novel mechanism how CD4 + T cells control CTL memory.Key words: CD27 Á CD4 T cell help Á Costimulation Á LCMV Á T cell memory IntroductionAfter an acute infection, the initial expansion of CTL is determined by a brief period of antigenic stimulation followed by a contraction to a stable pool of long-lived memory cells [1][2][3]. Memory CTL are characterized by an increased frequency of specific CD8 + T cells with a heightened sensitivity to an antigen that has been encountered previously. The cellular basis influencing memory CTL formation has been the focus of extensive research. Several studies highlighted the importance of CD4 + T cells in the generation of CTL memory [4][5][6]. Memory T lymphocytes that are primed in the absence of CD4 + T cell help have a reduced proliferation capacity. In addition, the production of acute effector cytokines and IL-2 are reduced [7]. "Unhelped" CD8 + T cells die upon in vitro re-activation, due to the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is not expressed by "helped" CD8 + memory T cells [8].The mechanisms how CD4 + T cell help drives CD8 + T cell memory has not been resolved in detail. Mice deficient for CD40L have CD8 + memory T cells with reduced function. The CD40-CD40L interaction may be involved in the generation of CTL memory via two mechanisms. First, CD4 + T cells expressing CD40L activate APC through CD40 and these "licensed" APC are then able to drive CD8 + T cell responses [9][10][11]. Secondly, CD4 + T cells expressing CD40L may directly deliver help to CD8 + T cells [7]. Besides the CD40-CD40L interaction, other receptor-ligand interactions such as the CD27-CD70 interaction may be important for generating functional CD8 + memory T cells [12]. In addition, soluble signals may be involved in CD8 + T cell formation. It has been reported that IL-4-secreting CD4 + T cells are involved in the formation of memo...

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“…CD4 + T cells are thought to provide help for CD8 + T cells, especially in response to non-inflammatory antigens via the regulation of TNF-related apoptosis-inducing ligand (TRAIL) [22]. CD8 + memory T cells generated without appropriate CD4 + help are defective in their abilities to respond in a recall response and undergo activation-induced cell death upon re-stimulation [14,22,23]. As the B cell helper function of CD4 + T cells exhibits age-related defects, it is likely that this defect also has an influence on the generation of functional CD8 memory T cells.…”

Section: Effect Of Age On Cd8 + T-cell-mediated Memorymentioning

confidence: 99%

The effect of aging on cognate function and development of immune memory

Haynes

2005

Current Opinion in Immunology

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Immunological memory is one of the central features of the immune system and can be described as the ability of the immune system to respond more efficiently to a second encounter with the same pathogen. The immune system is dramatically affected by age-related changes and it is becoming apparent that immune memory exhibits significant defects as a result of aging. Although immune memory generated during youth functions well into old age, that generated later in life functions poorly. Importantly, age-related defects in the cognate helper function of CD4 + T cells can potentially influence the development of both humoral and cell-mediated immune memory. These defects ultimately result in aged individuals who exhibit reduced responses to both infections and vaccinations.

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CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death

Cited by 560 publications

References 26 publications

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

CD4⁺ T cell help improves CD8⁺ T cell memory by retained CD27 expression

The effect of aging on cognate function and development of immune memory

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CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death

Cited by 560 publications

References 26 publications

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

Apoptosis mediated by lentiviral TRAIL transfer involves transduction-dependent and -independent effects

CD4+ T cell help improves CD8+ T cell memory by retained CD27 expression

The effect of aging on cognate function and development of immune memory

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CD4⁺ T cell help improves CD8⁺ T cell memory by retained CD27 expression