NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Wensveen, Felix M.; Lenartić, Maja; Jelenčić, Vedrana; Lemmermann, Niels A. W.; Brinke, Anja ten; Jonjić, Stipan; Polić, Bojan

doi:10.4049/jimmunol.1300670

Cited by 31 publications

(37 citation statements)

References 36 publications

(46 reference statements)

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“…A recent study showed that NKG2D enhances IL-15-mediated PI3K activation and promotes the survival of CD8 1 T cells. 39 Given that IL-15 signaling is critical in GVHD pathogenesis, 40 NKG2D expression by CD8…”

mentioning

confidence: 99%

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

Karimi¹,

Bryson²,

Richman³

et al. 2015

Blood

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• NKG2D enhances cytotoxicity and survival of CD8 1 T cells, which contributes to GVHD and GVT effects after allogeneic HSCT.• The temporally distinct expression pattern of NKG2D ligands may allow separation of GVHD and GVT effects by transient NKG2D blockade.In allogeneic hematopoietic stem cell transplantation (HSCT), controlling graft-versushost disease (GVHD) while maintaining graft-versus-tumor (GVT) responses is of critical importance. Using a mouse model of allogeneic HSCT, we hereby demonstrate that NKG2D expression by CD8 1 T cells plays a major role in mediating GVHD and GVT effects by promoting the survival and cytotoxic function of CD8 1 T cells. The expression of NKG2D ligands was not induced persistently on normal tissues of allogeneic HSCTrecipient mice treated with anti-NKG2D antibody, suggesting that transient NKG2D blockade might be sufficient to attenuate GVHD and allow CD8 1 T cells to regain their GVT function. Indeed, short-term treatment with anti-NKG2D antibody restored GVT effects while maintaining an attenuated GVHD state. NKG2D expression was also detected on CD8 1 T cells from allogeneic HSCT patients and trended to be higher in those with active GVHD. Together, these data support a novel role for NKG2D expression by CD8 1 T cells during allogeneic HSCT, which could be potentially therapeutically exploited to separate

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mentioning

confidence: 99%

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

Karimi¹,

Bryson²,

Richman³

et al. 2015

Blood

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“…BCL2 is expressed during memory formation, but knockout of BCL2 or BCLX does not abolish T-cell memory (20)(21)(22)(23)(24). Recent experiments are consistent with the possibility that MCL1 could have a role, as an association was observed between MCL1 stabilization and enhanced memory precursor frequency, induced through NKG2D signaling (25).…”

mentioning

confidence: 54%

“…Proapoptotic Noxa may also negatively regulate the memory T cell population size, as seen in influenza virus and cytomegalovirus infection experiments (34). In addition, a recent report on NKG2D gene knockout mice showed that NKG2D potentiates IL-15-mediated signaling through phosphoinositol 3-kinase, leading to increased MCL1 protein levels and enhanced survival of memory precursors (25). These findings, along with those presented here, suggest that, in addition to its functions promoting the survival of immature T cells and primary T cells, MCL1 may contribute to memory cell formation and/or survival.…”

Section: Discussionmentioning

confidence: 99%

MCL1 Enhances the Survival of CD8 ⁺ Memory T Cells after Viral Infection

Gui

Tsai

et al. 2015

J Virol

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Viral infection results in the generation of massive numbers of activated effector CD8؉ T cells that recognize viral components. Most of these are short-lived effector T cells (SLECs) that die after clearance of the virus. However, a small proportion of this population survives and forms antigen-specific memory precursor effector cells (MPECs), which ultimately develop into memory cells. These can participate in a recall response upon reexposure to antigen even at protracted times postinfection. Here, antiapoptotic myeloid cell leukemia 1 (MCL1) was found to prolong survival upon T cell stimulation, and mice expressing human MCL1 as a transgene exhibited a skewing in the proportion of CD8 ؉ T cells, away from SLECs toward MPECs, during the acute phase of vaccinia virus infection. A higher frequency and total number of antigen-specific CD8 ؉ T cells were observed in MCL1 transgenic mice. These findings show that MCL1 can shape the makeup of the CD8 ؉ T cell response, promoting the formation of long-term memory. IMPORTANCE During an immune response to a virus, CD8 ؉ T cells kill cells infected by the virus, and most die when the infection resolves. However, a small proportion of cells survives and differentiates into long-lived memory cells that confer protection from reinfection by the same virus. This report shows that transgenic expression of an MCL1 protein enhances survival of memory CD8 ؉ T cells following infection with vaccinia virus. This is important because it shows that MCL1 expression may be an important determinant of the formation of long-term CD8؉ T cell memory.U pon exposure to infectious agents, T cells undergo changes in gene expression that promote the generation and survival of effector cells, followed by the emergence of long-lived memory cells. The acute phase of virus infection results in the following sequence of events in CD8 ϩ T cells. A primary phase of clonal expansion generates cytolytic effector cells to facilitate elimination of the pathogen. This is followed by a contraction phase, during which a large number of potentially damaging cytotoxic effector cells undergo apoptosis. However, a number of cells survive this contraction and form the precursors of memory cells. Finally, during the memory phase, a small subset of antigen-specific CD8 ϩ T cells is maintained for an extended period, providing memory for later recall responses (1).While short-lived effector cells (SLECs) are important for the resolution of infection, memory precursor effector cells (MPECs) differentiate into the long-lived memory population (2). MPECs exhibit differences from SLECs in terms of phenotype and function (3). While both populations elaborate effector functions, MPECs have more subdued effector activity than SLECs (1, 4, 5). MPECs exhibit lower cell surface expression of the killer cell lectin-like receptor subfamily G member 1 (KLRG1) but higher expression of CD127 (IL-7R␣) (3). In contrast, SLECs exhibit higher KLRG1 but lower CD127 expression. In addition, interleukin-2 (IL-2) production is...

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“…Stimulation through the TCR is still required for activation of effector CD8 + T cells. In addition, continued activation of costimulatory receptors at the target + T cell memory responses [10][11][12][13][14][15][16]. It is likely that the differential activation of signal transduction pathways by CD28 and NKG2D receptors changes the gene expression profiles and functions of effector T cells, but the mechanisms of how this occurs are still unknown.…”

Section: Moj Immunologymentioning

confidence: 99%

Costimulation of Effector CD8+ T Cells: Which Receptor is Optimal for Immunotherapy?

Barber¹

2014

MOJI

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To induce strong immune responses, naive CD8 + T cells require stimulation through the TCR and costimulatory receptors. However, the biological consequence of activating costimulatory receptors on effector T cells is still unclear. In addition, activating CD8 + T cells either with vaccination or adoptive transfer of activated or gene-modified T cells are novel approaches for cancer and antiviral therapies. To enhance T cell efficacy, activation of costimulatory receptors is often incorporated in therapeutic designs; however it is still unclear how stimulation of different costimulatory receptors influences T cell function. Therefore it is essential to study how different costimulation receptors alter the gene expression and functions of activated CD8+ T cells. This will determine how combinations of costimulatory signals shape immunity and how to best activate and utilize these receptors for immunotherapy.

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NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Cited by 31 publications

References 36 publications

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

MCL1 Enhances the Survival of CD8 ⁺ Memory T Cells after Viral Infection

Costimulation of Effector CD8+ T Cells: Which Receptor is Optimal for Immunotherapy?

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NKG2D Induces Mcl-1 Expression and Mediates Survival of CD8 Memory T Cell Precursors via Phosphatidylinositol 3-Kinase

Cited by 31 publications

References 36 publications

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

NKG2D expression by CD8+ T cells contributes to GVHD and GVT effects in a murine model of allogeneic HSCT

MCL1 Enhances the Survival of CD8 + Memory T Cells after Viral Infection

Costimulation of Effector CD8+ T Cells: Which Receptor is Optimal for Immunotherapy?

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MCL1 Enhances the Survival of CD8 ⁺ Memory T Cells after Viral Infection