Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor.

Giri, Judith G.; Kumaki, Satoru; Ahdieh, Minoo; Friend, Della; Loomis, A. Katrina; Shanebeck, Kurt; DuBose, Robert; Cosman, David; Park, L. S.; Anderson, D

doi:10.1002/j.1460-2075.1995.tb00035.x

Cited by 576 publications

(463 citation statements)

References 45 publications

(79 reference statements)

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“…In addition, the site of IL-15 versus IL-2 protein or receptor chain expression and production was suggested to be mutually exclusive [34,[47][48][49]. Based on these data it was hypothesized that IL-2 and IL-15 might exert their effects at different stages of differentiation and/or on different populations of T or B lymphocytes [47,49]. Some in vivo differences might originate from the Ϸ 1000-fold higher affinity of IL-15 to its receptor a-chain in comparison to IL-2 binding affinity to the IL-2R a-chain in the absence of the common b-and g-chains [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

“…Based on these data it was hypothesized that IL-2 and IL-15 might exert their effects at different stages of differentiation and/or on different populations of T or B lymphocytes [47,49]. Some in vivo differences might originate from the Ϸ 1000-fold higher affinity of IL-15 to its receptor a-chain in comparison to IL-2 binding affinity to the IL-2R a-chain in the absence of the common b-and g-chains [47][48][49]. Whether this difference is of importance for in vivo situations remains to be elucidated, since affinity of both cytokines to the complete three chain receptor seems to be comparable [34].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, de Jong et al [57] recently showed that the IL-15/IL-2R b-/g-chain complex seems to be less stable than the IL-2/IL-2R b-/g-chain complex. In addition, the presence of high affinity IL-15 receptors on non-lymphoid tissue raises the question of whether IL-15 can induce intracellular signals in cells which do not express the common b-and g-chains [47]. Thus, one could hypothesize that binding of IL-15 to high affinity IL-15 a-chain on cells negative for IL-2/IL-15 b-and g-chains might serve for recruitment and activation of quiescent cells in an early phase of the inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

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Differential Role for IL‐2 and IL‐15 in the Inhibition of Apoptosis in Short Term Activated Human Lymphocytes

et al. 1997

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Lorenz H-M, Hieronymus T, Grünke M, Manger B, Kalden JR. Differential Role for IL-2 and IL-15 in the Inhibition of Apoptosis in Short Term Activated Human Lymphocytes. Scand J Immunol 1997;45:660-669 Interleukin (IL)-15 is a newly described cytokine with properties similar to IL-2. Even though it does not share sequence homology with IL-2, both cytokines bind to the same receptor with the noted exception of a cytokine specific a-chain. In this study the authors compared IL-2 and IL-15 to determine their ability to rescue short term activated lymphocytes (phytohaemagglutinin stimulation of peripheral blood mononuclear cells for 6 days, followed by expansion in medium containing IL-2 for 2 days) from apoptotic cell death. The authors found that both IL-2 and IL-15 can inhibit induction of apoptosis in this experimental model with similar time and dose kinetics. On mRNA or protein levels induction of pro-and anti-apoptotic gene products like fasL, bcl-2, or bax with minor effects on fas/Apo-1 or bcl-x L was observed under culture conditions with both IL-2 and IL-15. Next, it was found that phytohaemagglutinin (PHA) blasts were less responsive (in terms of cellular proliferation and prevention from apoptosis) to IL-2 if signals through the a-chain were blocked, with no effect on b-chain specific monoclonal antibodies (MoAb). By contrast, IL-15 was less effective in induction of cellular proliferation and prevention of apoptosis if IL-2R b-chain specific MoAb were added to cell cultures. Testing intracellular signalling induced by IL-2 or IL-15, the authors found identical changes in tyrosine phosphorylation patterns in PHA blasts cultured in medium or under IL-2 or IL-15 stimulation. By contrast, they found consistent differences if PHA stimulated peripheral blood mononuclear cells (PBMC) were expanded in medium containing IL-15 (instead of IL-2). These IL-15 expanded PHA blasts showed a significantly increased percentage of apoptosis after growth factor withdrawal. Furthermore, IL-2 was more efficient than IL-15 in rescuing IL-15 expanded PHA blasts from apoptosis. In IL-15 expanded PHA blasts expression of IL-2R a-chain was lower than that in IL-2 expanded PHA blasts. A model presenting a differential role for IL-2 and IL-15 in inhibition of apoptosis in vivo is discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differential Role for IL‐2 and IL‐15 in the Inhibition of Apoptosis in Short Term Activated Human Lymphocytes

et al. 1997

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“…Cytotoxicity was assessed by a 51 Cr release assay as described previously (28). YAC-1 cells (Cell Bank of Chinese Science Academy), which are lymphoma cells generally used to test the natural cytotoxicity of NK cells, were used as target cells.…”

Section: Cr Release Assaymentioning

confidence: 99%

Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

Zhou

Wei

Sun

et al. 2007

The Journal of Immunology

116

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The role of TLRs on intestinal epithelial cells (IECs) is controversial, and the mechanisms by which TLRs influence mucosal homeostasis are obscure. In this study, we report that genomic dsRNA from rotavirus, and its synthetic analog polyinosinic-polycytidylic acid (poly(I:C)), induce severe mucosal injury in the small intestine. Upon engaging TLR3 on IECs, dsRNA triggers IECs to secrete IL-15, which functions to increase the percentage of CD3+NK1.1+ intestinal intraepithelial lymphocytes (IELs) and enhances the cytotoxicity of IELs. Moreover, The CD3+NK1.1+ IELs are proved as CD8αα+ IELs. These results provide direct evidence that abnormal TLR3 signaling contributes to breaking down mucosal homeostasis and the first evidence of pathogenic effects mediated by CD8αα+ IELs. The data also suggest that genomic dsRNA may be involved in the pathogenesis of acute rotavirus gastroenteritis.

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“…The situation is somewhat different for the IL-15α receptors. There are far fewer of these IL-15α's per T cell [20,21] and the intracellular signaling is less well defined. These differences between high affinity receptors for IL-2 vs. IL-15 contribute to differential T cell growth responses and might be expected to cause differences between the two cytokines for induction of cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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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Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor.

Cited by 576 publications

References 45 publications

Differential Role for IL‐2 and IL‐15 in the Inhibition of Apoptosis in Short Term Activated Human Lymphocytes

Differential Role for IL‐2 and IL‐15 in the Inhibition of Apoptosis in Short Term Activated Human Lymphocytes

Recognition of Double-Stranded RNA by TLR3 Induces Severe Small Intestinal Injury in Mice

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

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