The IL-2 Receptor β Chain (p70): Role in Mediating Signals for LAK, NK, and Proliferative Activities

Siegel, Jay P.; Sharon, Michael; Smith, Paula

doi:10.1126/science.3116668

Cited by 430 publications

(213 citation statements)

References 30 publications

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“…7 Because the expression of CD25 is regulated by IL-2, 19 it can be imagined that blocking IL-2 production or signaling can interfere with CD25 expression and subsequently with T REG physiology. We therefore analyzed the proportion of CD4 þ CD25 þ T cells, with special focus on the CD25 high population, in spleen, lymph nodes and peripheral blood after mice were treated for 7 days with CsA or rapamycin.…”

Section: Csa Results In Cd25mentioning

confidence: 99%

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

Coenen

Koenen

Rijssen

et al. 2007

Bone Marrow Transplant

146

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Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3 þ regulatory T-cell (T REG ) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T REG homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T REG homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4 þ CD25 þ FoxP3 þ T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25 þ FoxP3 þ T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4 þ FoxP3 þ T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4 þ FoxP3 þ T REG in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.

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Section: Csa Results In Cd25mentioning

confidence: 99%

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

Coenen

Koenen

Rijssen

et al. 2007

Bone Marrow Transplant

146

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“…Differences in timing might explain the apparently divergent results with anti-CD25 antibodies which have been found to have either no effect on LAK induction (Tsudo et al, 1987) or to cause a partial blocking of LAK induction (Grimm et al, 1983;Shau et al, 1988). While the inhibition of LAK cytotoxicity by anti-CD25 is often marginal and much less pronounced than the inhibition of IL-2 induced lymphocyte proliferation (Siegel et al, 1987), the combination of anti-CD25 and antibodies specific for IL-2R-beta chain caused much greater inhibition of LAK than the latter alone (Phillips et al, 1989). This evidence suggests that CD25 does have some importance in the generation of LAK function.…”

Section: Resultsmentioning

confidence: 65%

“…When IL-4 was added 24 h or more after IL-2, no significant inhibition was observed. (Siegel et al, 1987) and CD56 (Ramsdell et al, 1988). Therefore, we examined the effect of IL-4 on the expression of these two activation markers to determine whether IL-4 can influence these IL-2 induced changes.…”

Section: Resultsmentioning

confidence: 99%

IL-1 and IL-4 as reciprocal regulators of IL-2 induced lymphocyte cytotoxicity

Ebina

Gallardo²,

Shau³

et al. 1990

Br J Cancer

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Summary Interleukin 4 (IL-4) suppresses the interleukin 2 (IL-2) induced lymphokine-activated killer (LAK) cell development from human peripheral blood mononuclear cells (PBMC). Suppression is observed at high (1,000 U ml-') as well as low (10 U ml-') concentrations of IL-2. IL-4 needs to be present at the beginning of the IL-2 culture to exert the suppressive effect. IL-4 also inhibits the development of CD25 (Tac) antigen on the PBMC cultured in IL-2. Interleukin I (IL-1) can reverse the suppressive effect of IL-4 on LAK induction when added at the early phase of the IL-2 culture. IL-I enhances IL-2 induced LAK development, which may partially explain the reversion of IL-4 inhibition by IL-1. IL-1 also reverses the inhibitory effect of IL-4 on the development of CD25 antigen expression, although IL-1 alone does not enhance the induction of CD25 expression in PBMC cultured by IL-2. Furthermore, IL-4 suppresses IL-2 induced IL-1 production in PBMC. Thus, suppression of CD25 may be a pathway for the suppression of LAK induction. The expression of CD56 is not directly associated with the expression of LAK activity. IL-4, IL-1 or combination of the two cytokines has no effect on IL-2 induced expression of CD56. These results indicate that IL-4 has an antagonistic effect and IL-1 has a synergistic effect on IL-2-induced LAK development.Interleukin 4 (IL-4) has pleiotropic regulatory effects on components of immune system including resting B cells, macrophages, mast cells, thymocytes (Gause et al., 1988) and peripheral T cells (Brown et al., 1988;Kern et al., 1988). Murine IL-4 can induce lymphokine activated killer (LAK) function (Mule et al., 1987;Peace et al., 1988) and also acts synergistically with interleukin 2 (IL-2) in LAK development (Mule et al., 1989 al., 1988).Recently, it has been shown that IL-4 inhibits the secretion of interleukin 1 (IL-1) from macrophages (Essner et al., 1989), and IL-1 has been reported to promote IL-2 dependent LAK development (Crump et al., 1989). Therefore, we sought to define the manner in which IL-4 can suppress IL-2 induced LAK induction, and to determine if IL-1 can reverse the IL-4 mediated suppression of LAK induction. To approach these questions, we examined the effect these cytokines on modulation of cytotoxicity and on the expression of IL-2 activation markers such as CD25 (Tac) and CD56 (NKH1). Materials and methods Cell preparation and tymphocyte culture

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“…Using radioiodinated IL-2 and chemical cross-linking methodology, a non-Tac IL-2 binding protein of 70/75 kDa has been identified [8,9]. The p70/75 IL-2R expressed on LGL cells has an intermediate affinity for IL-2 in itself but is capable of transducing the signal of IL-2 [10]. It has been proposed that the p70/75 IL-2R associates with the p55 IL-2R to form the highaffinity IL-2R complex and has a domain responsible for the signal transduction of IL-2.…”

Section: Introductionmentioning

confidence: 99%

Murine interleukin‐2 receptor subunits differentially detected with anti‐interleukin‐2 monoclonal antibodies

Takemoto

1989

FEBS Letters

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Cross-linking of radioiodinated interleukin-2 to murine CTLL-2 cells enabled detection of 70 kDa, 85 kDa and 105 kDa complexes of IL-2 and its binding proteins under the high-affinity binding condition. A series of anti-interleukin-2 monoclonal antibodies (L15, L20, L23, L34, and L61) were tested for their activity to immunoprecipitate these cross-linked complexes. L6 I, which had strong neutralizing activity, precipitated only the 70 kDa complex. L 15, L20, and L34, which also had neutralizing activity, precipitated not only the 70 kDa complex but also the 85 kDa complex. L23, which had practically no neutralizing activity, precipitated the 105 kDa complex as well as the 85 kDa complex. These results suggest that there are at least three distinct receptor binding sites for each receptor subunit on the interleukin-2 molecule, which are discernible by these monoclonal antibodies and that the 105 kDa complex may play a significant role in the formation of the high-affinity receptor complex and the signal transduction.

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The IL-2 Receptor β Chain (p70): Role in Mediating Signals for LAK, NK, and Proliferative Activities

Cited by 430 publications

References 30 publications

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

IL-1 and IL-4 as reciprocal regulators of IL-2 induced lymphocyte cytotoxicity

Murine interleukin‐2 receptor subunits differentially detected with anti‐interleukin‐2 monoclonal antibodies

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