Contrasting Roles of IL-2 and IL-15 in the Life and Death of Lymphocytes Implications for Immunotherapy

Waldmann, Thomas A.; Dubois, Sigrid; Tagaya, Yutaka

doi:10.1016/s1074-7613(09)00091-0

Cited by 278 publications

(320 citation statements)

References 22 publications

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“…IL-2 has been used for immunotherapy with some success but, for multiple reasons, clinicians might hope for improved responses with IL-15 [66]. Unfortunately for immunotherapy, our results suggest that high IL-15 may cause some of the same problems that IL-2 does.…”

Section: Discussionmentioning

confidence: 77%

“…IL-15 is considered a "memory" cytokine, driving homeostatic replacement of memory lymphocytes [29,30,31,32]. It is important to know whether naive as well as memory T cells acquire granzyme B when cytokine-stimulated and also if the cells can respond without dividing.…”

Section: Grz B+ Cd8+ T Cells Are Also Cd44 Hi Cd122 + and May Acquirementioning

confidence: 99%

“…IL-2 and IL-15 are T cell growth factors that support adaptive immune responses [9,10]. Both cytokines share a pair of receptor subunits, the gamma chain common to several cytokine receptors (γ c , CD132) combined with the IL-2/15 beta receptor chain (IL-2Rβ, CD122) [11]. Binding of either IL-2 or IL-15, with Kd's ~10 −9 M [12, 13,14], will activate this dimeric receptor to transmit intracellular signals via the JAK1/3-STAT3/5 pathways [15,16,17].…”

Section: Introductionmentioning

confidence: 99%

“…There are substantial numbers of these CD122/CD132 receptors on T cells and, at high concentrations (10 −8 M) of either IL-2 or IL-15, these receptors will be saturated. IL-2 and IL-15 each have specific high affinity receptors (Kd ~ 10 −11 M) that are formed when separate specific alpha receptor chains combine into trimeric receptors with the CD122/CD132 pair [18,19]. The IL-2Rα chain (CD25) in its trimer is thought to mediate subsequent signaling via the CD122/CD132 pair.…”

Section: Introductionmentioning

confidence: 99%

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Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

et al. 2006

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The purpose of these studies was to determine the minimal requirements to induce granzyme B, cytotoxic granules and perforin-dependent lytic capacity. To our surprise, both IL-2 and IL-15 induced not only proliferation, but also profound granzyme B and lytic capacity from CD8 + T cells in the absence of antigen or TCR-stimulation. Mouse splenocytes were incubated with mouse r-IL-2 or r-IL-15 for three days, tested by anti-CD3 redirected lysis and examined for intracellular granzyme B and for T cell activation markers. With 10 −8 M IL-2 or IL-15, there was excellent lytic activity at 1:1 effector to target ratios mediated by T cells from wild type but not from perforin-gene-ablated mice, consistent with multiclonal activation. Lower interleukin concentrations induced less lytic activity. Granzyme B was undetectable on day 0, and greatly elevated on day 3 in CD44 hi CD8 + T cells as detected by flow cytometry. Cytokines alone elevated the granzyme B as much as concanavalin A combined with the cytokines. Some ex vivo CD8 + T cells were CD122 + , as were the cultured granzyme B + cells, thus both populations had low affinity receptors for the interleukins. Only some of the activated cells were proliferating as detected by CFSE labeling. When the cytokines were withdrawn, the cells lost lytic activity within 24 hours and then within the next 24 hours, died. Our results suggest that high concentrations of either IL-2 or IL-15 will activate the lytic capacity and granzyme B expression of many T cells and that antigen recognition is not required.

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Section: Discussionmentioning

confidence: 77%

Section: Grz B+ Cd8+ T Cells Are Also Cd44 Hi Cd122 + and May Acquirementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

et al. 2006

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“…IL-2 and IL-15 signaling involves engagement of the JAK-STAT pathways [112,113]. Additionally IL-2 and IL-15 also engage the phosphatidylinositol-3-kinase–AKT pathway as well as the Ras/Raf/Erk and p38 MAPK pathways, which play important roles in mediating the biological effects of these cytokines [114–116].…”

Section: Rantesmentioning

confidence: 99%

Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

et al. 2005

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Cytokine immunotherapy using interleukin (IL)-2 and IL-15 may be beneficial for patients receiving umbilical cord blood (CB) transplantation by ameliorating post-transplant T-cell apoptosis. The present study compares the differential effect of IL-15 and IL-2 on survival of phytohemagglutinin (PHA)-activated CB and adult peripheral blood (APB) T lymphocytes. In comparison with IL-2, IL-15 preferentially enhanced the survival of CB PHA-activated T cells by decreasing the caspase-3 + population and by increasing the Bcl-2 + population. Activated CB T cells were more susceptible to TNF-a-induced apoptosis compared to their adult counterparts. However, the susceptibility could be abrogated by IL-15 but not by IL-2. IL-15 but not IL-2 down-regulated CD28 expression on both activated CB and APB CD8 + T cells, with a much greater effect seen with CB. Westernblot analysis shows that IL-15 Ra is deficient in CB compared to APB immediately after PHA stimulation, while culturing with IL-15 significantly enhanced CB IL-15 Ra expression to levels comparable to that of adults. Thus, IL-15 may provide a better therapeutic choice for immune reconstitution than IL-2 post-CB transplantation due to its preferential survival enhancing effect on CB T cells. Am.

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Contrasting Roles of IL-2 and IL-15 in the Life and Death of Lymphocytes Implications for Immunotherapy

Cited by 278 publications

References 22 publications

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

Mnk kinases in cytokine signaling and regulation of cytokine responses

Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

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