Signaling T‐Cell Survival and Death by IL‐2 and IL‐15

Zambricki, Elizabeth A.; Shigeoka, Alana A.; Kishimoto, Hiroyuki; Sprent, J.; Burakoff, Steven J.; Carpenter, Charles B.; Milford, Edgar L.; McKay, Dianne B.

doi:10.1111/j.1600-6143.2005.01075.x

Cited by 47 publications

(43 citation statements)

References 58 publications

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“…The pathways involved in IL-15 signaling include JAK/STAT and PI3K/AKT (17,18). The PI3K/ AKT pathway also participates in TCR signaling (22).…”

Section: The Restoration Of Impaired Tcr-mediated Proliferation Of Humentioning

confidence: 99%

“…17). The Department of Internal Medicine, Section of Rheumatology, Yale University School of Medicine, New Haven, CT 06520 recognition of IL-15 by the latter receptor chains leads to the activation of various signaling pathways including JAK1 and 3/STAT5 as well as PI3K/AKT (protein kinase B) (18). IL-15 has diverse functions that include promoting cytotoxicity and maintenance of memory CD8 ϩ T cells as well as proliferation and differentiation of NK and NK T cells (17 …”

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confidence: 99%

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Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway

Kim

Hwang

Kang

2007

The Journal of Immunology

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Recently, we identified two subsets of CCR7− memory CD8+ T cells expressing high and low levels of the IL-7R α-chain (IL-7Rα) that is essential for memory T cell survival in human peripheral blood. IL-7RαlowCCR7− memory CD8+ T cells that produce effector cytokines and perforin have impaired proliferation and survival in response to TCR triggering and IL-7, respectively. These findings raise a question of how such cells are sustained at significant numbers, >20% of peripheral CD8+ T cells, despite impaired IL-7- and TCR-mediated cell maintenance. In this study, we demonstrate that IL-7RαlowCCR7− memory CD8+ T cells have increased expression of IL-2/15R β-chain (IL-2/15Rβ), which is critical for IL-15 signaling, with enhanced gene expression of T box expressed in T cells (T-bet) and eomesodermin (eomes), transcriptional factors involved in IL-2/15Rβ expression compared with IL-7RαhighCCR7− memory CD8+ T cells. Such a cytokine chain is functional as IL-7RαlowCCR7− memory CD8+ T cells proliferate considerably in response to IL-15. Furthermore, adding IL-15 to TCR triggering recovers impaired TCR-mediated proliferation of IL-7Rαlow memory CD8+ T cells via restoring the activation of the PI3K/AKT pathway. These findings indicate that IL-15 has dual roles in maintaining IL-7RαlowCCR7− memory CD8+ T cells via TCR-dependent and -independent mechanisms. Moreover, IL-15 can be useful in reviving impaired proliferative function of such memory CD8+ T cells with effector functions against infections and tumors via rescuing the PI3K/AKT pathway.

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“…The pathways involved in IL-15 signaling include JAK/STAT and PI3K/AKT (17,18). The PI3K/ AKT pathway also participates in TCR signaling (22).…”

Section: The Restoration Of Impaired Tcr-mediated Proliferation Of Humentioning

confidence: 99%

mentioning

confidence: 99%

Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway

Kim

Hwang

Kang

2007

The Journal of Immunology

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“…16,17 The IL-2R␤ and ␥ c chains signal through the JAK1 and JAK3 tyrosine kinases, which activate downstream STAT pathways. 18,19 In addition to the IL-2R␤/␥ c complex, specific 21 molecules are required for high-affinity binding of each cytokine. Unlike IL-2R␣, IL-15R␣ is a high-affinity receptor also when expressed as an isolated chain, and is present on both lymphoid and nonlymphoid cell types.…”

mentioning

confidence: 99%

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

Totero

Meazza

Capaia

et al. 2008

Blood

108

103

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The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common ␥ chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and pre- IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in adults, is characterized by the progressive accumulation of CD5 ϩ neoplastic B cells, 1-3 which results from a dynamic balance between cell death and proliferation. 3,4 The finding that purified CLL cells do not proliferate and tend to undergo spontaneous apoptosis in vitro suggests that factors inducing CLL cell survival and proliferation might be present in the microenvironment of lymphoid organs or of the bone marrow. 5,6 Several cytokines such as the TNF family members BAFF and APRIL, 7,8 the chemokine SDF-1, 9,10 and interleukin-2 (IL-2) 11,12 and IL-15 13 stimulate CLL cell proliferation and/or survival in vitro. IL-2 and IL-15 share the usage of the IL-2R␤ (CD122) and of the common ␥ chain (␥ c ; CD132) 14,15 and thus have similar functional effects on IL-2R␤/␥ c ϩ cells. 16,17 The IL-2R␤ and ␥ c chains signal through the JAK1 and JAK3 tyrosine kinases, which activate downstream STAT pathways. 18,19 In addition to the IL-2R␤/␥ c complex, specific 21 molecules are required for high-affinity binding of each cytokine. Unlike IL-2R␣, IL-15R␣ is a high-affinity receptor also when expressed as an isolated chain, and is present on both lymphoid and nonlymphoid cell types. 20,21 IL-15R␣ is crucial for IL-15 activity, since both IL-15-and IL-15R␣-deficient mice display similar defects in the development of natural killer (NK) cells, of intraepithelial T lymphocytes, and of CD8 ϩ memory-type T cells. 22,23 IL-15 gene is expressed in several tissues, and IL-15 can be either secreted in low amounts or displayed as a membrane-bound cytokine by several cell types. [24][25][26][27][28] Therefore IL-15 is considered a microenvironmental factor, which supports lymphoid cell homeostasis and survival. 29-31 IL-15 is a growth or survival factor not only for CLL cells 13 but also for cells of other lymphoid neoplasias, 32-34 at least in vitro. Moreover, in IL-15-transgenic mice, IL-15 overexpression induces fatal T or NK lymphoproliferative disorders. 35 We and others recently demonstrated that IL-21, the last identified member of the IL-2 family, 36-38 is unable to trigger CLL cell proliferation, but rather induces their apoptosis. 39,40 This effect is potentiated by cell activation with CD40L, 39 with CpG synthetic oligonucleotides, or by BCR cross-linking. 40 IL-21 induces the JAK1 and JAK3 and the STAT1, STAT3, and STAT5 tyrosine phosphorylation in CLL B cells. 39 Similar early signaling events are also activated by IL-21, IL-2, or IL-1...

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“…30,31 It was also reported that both IL-2 and IL-15 could induce apoptosis and survival, with the outcome depending on cytokine concentration. 32 Other cytokines, such as IL-15 and IL-21, as well as co-stimulatory molecules such as 4-1BBL and CD80, have been reported to promote CD8 þ memory T-cell survival by pathways independent of the stimulation of regulatory T cells 33 and of effects on the human telomerase gene that counteract the loss of proliferative potential. 34 A number of reports from clinical studies that used scFv-engineered T cells have highlighted the efficacy of genetic modification of T cells, mostly mediated by retro-or lentivirus.…”

Section: Discussionmentioning

confidence: 99%

Direct and indirect antitumor effects by human peripheral blood lymphocytes expressing both chimeric immune receptor and interleukin-2 in ovarian cancer xenograft model

Lee

et al. 2010

Cancer Gene Ther

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Human peripheral blood lymphocytes (PBLs) electroporated with RNA encoding anti-Her-2/neu-specific chimeric immune receptor (CIR) have been reported to elicit potent immune responses against SKOV3 tumors in a nude mouse model. However, CIRelectroporated PBL (CIR-PBL) did not proliferate, and the cell number rapidly decreased in the absence of exogenous interleukin-2 (IL-2). In this study, PBLs electroporated with both CIR and IL-2 RNA (CIR/IL-2-PBL) were studied to determine whether antitumor effects could be improved by adoptive immunotherapy. CIR and IL-2 were expressed in CIR/IL-2-PBL at levels similar to PBLs electroporated, with IL-2 RNA (IL-2-PBL) or CIR-PBL. Transfer of IL-2 RNA induced proliferation and prolonged survival of PBLs in vitro. In a xenograft model, both IL-2-PBL and CIR/IL-2-PBL showed significantly higher antitumor effects than CIR-PBL. The number of tumor-infiltrating natural killer (NK) cells was significantly increased in IL-2-PBL and CIR/IL-2-PBL. After NK cell depletion, IL-2-PBL showed significantly lower antitumor effects than CIR/IL-2-PBL. These results suggest that transfer of IL-2 RNA to CIR-PBL can promote NK cell infiltration of tumors and prolong survival of infused PBLs in vivo. RNA electroporated PBLs may represent efficient tools for delivery of functional molecules to tumors by multiple gene transfer.

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Signaling T‐Cell Survival and Death by IL‐2 and IL‐15

Cited by 47 publications

References 58 publications

Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway

Dual Roles of IL-15 in Maintaining IL-7RαlowCCR7− Memory CD8+ T Cells in Humans via Recovering the Phosphatidylinositol 3-Kinase/AKT Pathway

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

Direct and indirect antitumor effects by human peripheral blood lymphocytes expressing both chimeric immune receptor and interleukin-2 in ovarian cancer xenograft model

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