IL-2R Beta Chain Research Articles

Interleukin-2 Controls flt3L-dependent Development and Phenotype of Conventional and Plasmacytoid Dendritic Cells (36.19)

Abstract DC development requires the ligand for FMS-like tyrosine kinase 3 receptor (flt3L), but little is known regarding other cytokines that may control this process. In our study, we have addressed the effect of IL-2 on DC development. We have shown that the addition of IL-2 to flt3L-stimulated bone marrow (BM) cultures can block the development of both pDCs (CD11c+SiglecH+) and cDCs (CD11c+CD11b+), while expanding the populations of NK/NKT/T cells (CD3+/-NK1.l+/-). By sorting for DC precursors that are Lineage- flt3+ CD11c-, we confirm that IL-2 blocks DC development by acting directly on DC precursors, and not indirectly via its effect on NK/NKT/T cells. The inhibition of DC development by IL-2 is dependent on both the IL-2R alpha and beta chains, and STAT5. IL-2 treatment of DC precursors leads to a decrease in the expression of various transcription factors crucial for DC development. In addition, our ongoing studies indicate that the presence of IL-2 during flt3L-dependent DC development also alters the phenotype of DCs. Together our data has indicated that IL-2 inhibits the development of DCs, and suggests IL-2 can also alter DC phenotype. This has important implications in the therapeutic use of IL-2, as well as our current understanding on factors that can lead to the loss of immune tolerance in various autoimmune diseases.

A Low Interleukin-2 Receptor Signaling Threshold Supports the Development and Homeostasis of T Regulatory Cells

Interleukin-2 receptor (IL-2R) signaling is essential for T regulatory (Treg) cell development and homeostasis. Here, we show that expression of IL-2Rbeta chains that lack tyrosine residues important for the association of the adaptor Shc and the transcription factor STAT5 in IL-2Rbeta-deficient mice resulted in production of a normal proportion of natural Treg cells that suppressed severe autoimmunity related with deficiency in IL-2 or IL-2R. These mutant IL-2Rbeta chains supported suboptimal and transient STAT5 activation that upregulate the transcription factor Foxp3 to normal amounts in natural, but not induced, Treg cells. Nevertheless, gene expression profiling revealed many targets in peripheral natural Treg cells that were IL-2 dependent and a substantial overlap between the Treg cell IL-2-dependent gene program and the Treg cell transcriptional signature. Collectively, these findings demonstrate that a critical, and perhaps minor, subset of IL-2-dependent targets is indexed to a low IL-2R signaling threshold and that a substantial proportion of the Treg cell gene program is regulated by IL-2.

Differential Regulation of the IL-17 Receptor by γc Cytokines: INHIBITORY SIGNALING BY THE PHOSPHATIDYLINOSITOL 3-KINASE PATHWAY

The gammac-family cytokine IL-2 activates signaling events that contribute to cell survival and proliferation, the best-studied of which are the STAT-5 and phosphatidylinositol 3-kinase (PI3K) pathways. The starting point of this study was to define genes regulated by the IL-2R-mediated PI3K pathway in T cells. Accordingly, we used an erythropoietin (EPO) receptor chimeric receptor system in which IL-2-dependent HT-2 T cells expressed a mutant EPO-IL-2Rbeta construct where Tyr-338 is mutated to Phe. Cells expressing this mutant IL-2Rbeta chain fail to induce phosphorylation of PI3K-p85alpha/beta or activate Akt, but mediate normal IL-2-dependent proliferation and activation of JAK1 and STAT-5A/B. Microarray analyses revealed differential regulation of numerous genes compared with cells expressing a wild-type IL-2Rbeta, including up-regulation of the IL-17 receptor subunit IL-17RA. Blockade of the PI3K pathway but not p70S6K led to up-regulation of IL-17RA, and constitutive Akt activation was associated with suppressed IL-17RA expression. Moreover, similar to the mutant EPO-IL-2Rbeta chimera, IL-15 and IL-21 induced IL-17RA preferentially compared with IL-2, and IL-2 but not IL-15 or IL-21 mediated prolonged activation of the PI3K p85 regulatory subunit. Thus, there are intrinsic signaling differences between IL-2 and IL-15 that can be attributed to differences in activation of the PI3K pathway.

Human IL-Rbeta chains form IL-2 binding homodimers.

Two types of functional interleukin-2 receptor (IL-2Ralpha/IL-2Rbeta/gammac and IL-2Rbeta/gammac) have already been characterized in humans. Here we describe a new form consisting of IL-2Rbeta/beta homodimers that assemble spontaneously in the absence of gammac. Co-transfection of COS-7 cells with constructs expressing IL-2Rbeta chains tagged with either HA or MYC sequences results in the formation of IL-2Rbeta:HA/IL-2Rbeta:MYC complexes detectable by coimmunoprecipitation. The formation of these IL-2Rbeta:HA/IL-2Rbeta:MYC dimers is also observed in the absence of IL-2. Moreover, in COS cells expressing chimeras of IL-2Rbeta fused to fluorescence reporters such as IL-2Rbeta:ECFP and IL-2Rbeta:EYFP, we also observed specific FRET at the surface of living cells, as expected for dimer formation. Transiently transfected COS-7 cells expressing IL-2Rbeta bind 125I-labeled IL-2 (homodimers, Kd = 1nM) as cells expressing both IL-2Rbeta and gammac chains (heterodimers, Kd = 1 nM). IL-2Rbeta/IL-2Rbeta could represent either a decoy receptor or a new form of IL-2R involved in signaling when gammac expression is low.

Interleukin 4: signalling mechanisms and control of T cell differentiation.

Interleukin 4 (IL-4) is a pleiotropic type I cytokine that controls both growth and differentiation among haemopoietic and non-haemopoietic cells. Its receptor is a heterodimer. One chain, the IL-4R alpha chain, binds IL-4 with high affinity and determines the nature of the biochemical signals that are induced. The second chain, gamma c, is required for the induction of such signals. IL-4-mediated growth depends upon activation events that involve phosphorylation of Y497 of IL-4R alpha, leading to the binding and phosphorylation of 4PS/IRS-2 in haemopoietic cells and of IRS-1 in non-haemopoietic cells. By contrast, IL-4-mediated differentiation events depend upon more distal regions of the IL-4R alpha chain that include a series of STAT-6 binding sites. The distinctive roles of these receptor domains was verified by receptor-reconstruction experiments. The 'growth' and 'differentiation' domains of the IL-4R alpha chain, independently expressed as chimeric structures with a truncated version of the IL-2R beta chain, were shown to convey their functions to the hybrid receptor. The critical role of STAT-6 in IL-4-mediated gene activation and differentiation was made clear by the finding that lymphocytes from STAT-6 knockout mice are strikingly deficient in these functions but have retained the capacity to grow, at least partially, in response to IL-4. IL-4 plays a central role in determining the phenotype of naive CD4+ T cells. In the presence of IL-4, newly primed naive T cells develop into IL-4 producers while in its absence they preferentially become gamma-interferon (IFN-gamma) producers. Recently, a specialized subpopulation of T cells, CD4+/NK1.1+ cells, has been shown to produce large amounts of IL-4 upon stimulation. Two examples of mice with deficiencies in these cells are described--beta 2-microglobulin knockout mice and SJL mice. Both show defects in the development of IL-4-producing cells and in the increase in serum IgE in response to stimulation with the polyclonal stimulant anti-IgD. Both sets of mice have major diminutions in the number of CD4+/ NK1.1+ T cells, strongly indicating an important role of these cells in some but not all IgE responses to physiologic stimuli.

Constitutive expression of IL-2Rbeta chain and its effects on IL-2-induced vascular leak syndrome

IL-2-induced vascular leak syndrome (VLS) is an important mechanism explaining the toxic effects of this cytokine and limiting its therapeutic use. We previously characterized a mouse model of IL-2-induced pulmonary VLS used to demonstrate that NK lymphocytes are involved in early/acute phase VLS (after one IL-2 injection). We also showed that NK cells and polymorphonuclear neutrophils (PMN) are involved in the late/chronic phase of the syndrome (after four daily IL-2 injections). In this study we use our mouse model to evaluate the role played by the IL-2 receptor (IL-2R) in VLS induction. Mouse and human IL-2R are different since the mouse IL-2Rbeta chain does not recognize IL-2. Here, we compare the acute and late VLS responses in human IL-2Rbeta transgenic and C57BL/6 wild type mice. Parameters linked to early phase VLS (bronchoconstriction and PMN mobilization) are enhanced in human IL-2Rbeta transgenic mice. By contrast, parameters used to measure late events (protein leakage and edema) are similar in human IL-2Rbeta transgenic mice and C57BL/6 wild type animals. However, after four IL-2 injections, the cellular content of the bronchoalveolar lavage fluids was different between the two types of animals. This study also characterizes a humanized animal model that could be further used to study human IL-2 activity and side effects in vivo.

Chagas' disease susceptibility/resistance: linkage disequilibrium analysis suggests epistasis between major histocompatibility complex and interleukin-10.

Association between the major histocompatibility complex (MHC) and the susceptibility/resistance to acquire Chagas' disease has been largely demonstrated. To study the role of candidate genes in this susceptibility/resistance to Chagas, we designed a population-genetic-based case-control approach (chagasic n = 104 and controls n = 60) and tested the presence of genotype and linkage disequilibrium on microsatellite loci establishing specific landmarks for the MHC, interleukin (IL)-2, IL-2Rbeta chain, IL-4, IL-10, and natural resistance-associated mactophage protein 1 (NRAMP1). After demonstrating no genetic stratification among cases and controls (F(st) were not different from 0), we found significant allelic differences among chagasic patients and controls at microsatellite locus D6S291 (MHC) and at the microsatellite pointing out the IL-10. At the MHC, we found significant differences between patients and controls in Hardy-Weinberg equilibrium-expected genotype proportions. Additionally, MHC II-locus-inferred haplotypes in chagasic patients exhibited strong significant departures from the expected proportions predicted by the second Mendelian law. The linkage disequilibrium pattern at MHC involves a region of approximately 10 cM. These results replicate previous analyses and suggest that presence of epistasis between MHC with humoral systems, such as IL-10, could be underlying the susceptibility/resistance to Chagas' disease.

Regulation of human short-term repopulating cell (STRC) engraftment in NOD/SCID mice by host CD122+ cells.

NOD/SCID and NOD/SCID B2m(null) mice are used for the in vivo study of human hematopoietic stem cells (HSC). A previously unrecognized HSC in cord blood, termed short-term repopulating cell (STRC), has been identified using NOD/SCID B2m(null) mice. However, only low levels of STRC engraft in NOD/SCID mice, presumably due to their higher levels of NK cell activity. The objective of these studies was to deplete NK cells both by genetic manipulation of the hosts and by antibody depletion of cell populations that may regulate engraftment with human STRC. C57BL/6-SCID mice and immunodeficient NOD mice genetically deleted in NK cell activity were injected intravenously with human cord blood cells to quantify STRC engraftment. Cohorts of these mice were also treated with anti-NK1.1 or anti-CD122 (IL-2r beta-chain) antibodies. Human STRC fail to engraft in C57BL/6-SCID mice treated with anti-NK1.1 or with anti-CD122 antibody that targets mouse NK and myeloid cells. NOD/SCID mice, NOD-Rag1(null) mice, and NOD-Rag1(null)Pfp(null) mice that are genetically deleted in NK cell cytotoxic activity support only low levels of STRC engraftment. In contrast, STRC engraft at high levels in all three strains of immunodeficient NOD mice treated with anti-CD122 antibody. Injection of anti-CD122 antibody leads to high levels of STRC engraftment in immunodeficient NOD mice, but not in C57BL/6-SCID mice. These data document that depletion of NK cells is required, and that additional murine host innate immune factors, presumably myeloid cells, are important in regulating human STRC engraftment.

Anti-apoptotic Signaling by the Interleukin-2 Receptor Reveals a Function for Cytoplasmic Tyrosine Residues within the Common γ (γc) Receptor Subunit

The interleukin-2 receptor (IL-2R) is composed of one affinity-modulating subunit (IL-2Ralpha) and two essential signaling subunits (IL-2Rbeta and gammac). Although most known signaling events are mediated through tyrosine residues located within IL-2Rbeta, no functions have yet been ascribed to gammac tyrosine residues. In this study, we describe a role for gammac tyrosines in anti-apoptotic signal transduction. We have shown previously that a tyrosine-deficient IL-2Rbeta chain paired with wild type gammac stimulated enhancement of bcl-2 mRNA in IL-2-dependent T cells, but it was not determined which region of the IL-2R or which pathway was activated to direct this signaling response. Here we show that up-regulation of Bcl-2 by an IL-2R lacking IL-2Rbeta tyrosine residues leads to increased cell survival after cytokine deprivation; strikingly, this survival signal does not occur in the absence of gammac tyrosine residues. These gammac-dependent signals are revealed only in the absence of IL-2Rbeta tyrosines, indicating that the IL-2R engages at least two distinct signaling pathways to regulate apoptosis and Bcl-2 expression. Mechanistically, the gammac-dependent signal requires activation of Janus kinases 1 and 3 and is sensitive to wortmannin, implicating phosphatidylinositol 3-kinase. Consistent with involvement of phosphatidylinositol 3-kinase, Akt can be activated via tyrosine residues on gammac. Thus, gammac mediates an anti-apoptotic signaling pathway through Akt which cooperates with signals from its partner chain, IL-2Rbeta.

The IL-15R alpha chain signals through association with Syk in human B cells.

The alpha-chain of the IL-15R (IL-15Ralpha) serves as the specific, high-affinity receptor for IL-15. It is expressed by lymphoid and nonlymphoid cells, including B cell lymphoma lines. In this study, we have further explored IL-15Ralpha-mediated signaling in activated primary B cells and in Raji cells, a human B-lymphoblastoid cell line which expresses the IL-15Ralpha and IL-2Rgamma chains, but lacks the IL-2Rbeta chain. Stimulation of Raji cells with IL-15 induces their proliferation and rescues them from C2-ceramide-induced apoptosis. By immunoprecipitation and Western blotting, we show that treatment of Raji cells and activated primary B cells with IL-15 induces coprecipitation of Syk kinase with the IL-15Ralpha chain. Upon association, the activated Syk kinase phosphorylates the IL-15Ralpha chain as well as phospholipase Cgamma, which coprecipitates with Syk. Furthermore, transfection of Raji cells with stem-loop Syk antisense oligonucleotides prevents IL-15Ralpha and phospholipase Cgamma phosphorylation as well as the inhibition of apoptosis by IL-15. Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells.

Dysregulated expression of CD69 and IL-2 receptor alpha and beta chains on CD8+ T lymphocytes in flaky skin mice.

T-cell activation is considered to be an important element in the pathogenesis of psoriasis, a human skin disease characterized by keratinocyte hyperproliferation, altered keratinocyte differentiation and inflammation of the dermis and epidermis. Mice homozygous for the flaky skin (fsn) mutation develop a skin disorder that has histopathological and biochemical features resembling some forms of psoriasis. It has been reported recently that peripheral lymph nodes (PLN) in fsn/fsn mice exhibit various abnormalities in T-cell development suggestive of dysregulated T- and B-cell activation. In the present study, the expression of the inducible T-cell activation antigens CD69 and IL-2 receptor alpha chain (CD25) on PLN cells from fsn/fsn mice and their phenotypically normal littermates is examined. Expression of CD69 was significantly increased on PLN cells in fsn/fsn mice (mean +/- SD, 49.9 +/- 14.7% of cells) compared with control mice (14.6 +/- 4.2%). Analysis of CD4+ and CD8+ T cell subsets revealed that expression of CD69 in fsn/fsn PLN was significantly biased toward CD8+ cells. Although expression of CD25 was preferentially associated with CD4+ rather than CD8+ cells in both fsn/fsn and control PLN, with most CD4+ CD25+ cells being CD25hi, the proportion of CD4+ cells expressing CD25 was higher in fsn/fsn than control PLN. In contrast, CD25 was expressed by 2-3% of CD8+ PLN cells in both fsn/fsn and control mice and CD25hi cells accounted for < 1% of CD8+ cells in fsn/fsn PLN. The paucity of CD25 on CD8+ cells in fsn/fsn PLN did not appear to be due to a defect in the ability of these cells to upregulate CD25, because T cell receptor stimulation in vitro induced high expression of CD25 on both CD4+ and CD8+ cells. A striking and consistent finding was that most CD8+ cells in fsn/fsn PLN expressed high levels of IL-2R beta chain (CD122). In contrast, CD122 was expressed at low levels on CD8+ cells in control mice. Analysis of PLN cells from newborn fsn/fsn mice revealed that the high expression of CD122 on CD8+ cells was established by 2 weeks of age, prior to the appearance of clinical skin disease. These data indicate that large numbers of T cells in fsn/fsn mice are activated and reinforce the view that fsn is an important regulator of lymphocyte development and function. The relationship between T-cell activation and flaky skin disease in these mice remains to be established.

Characterization of human copine III as a phosphoprotein with associated kinase activity.

The copines, first described by Creutz et al. [(1998) J. Biol. Chem. 273, 1393-1402], comprise a two C2 domain-containing protein family and are known to aggregate phosphatidylserine membranes in a calcium-dependent manner. No enzymatic function has been attributed to copines yet. Due to a cross-reacting activity of Mikbeta1, an antibody to the IL-2Rbeta chain, we were able to serendipitously purify, partially microsequence, and clone human copine III. The 5 kb copine III transcript is expressed ubiquitously as determined by a multitissue Northern blot analysis. Phosphoamino acid analysis revealed phosphorylation of copine III on serine and threonine residues. In vitro kinase assays were performed with immunoprecipitated endogenous copine III, chromatography-purified endogenous copine III, and recombinant copine III expressed in Saccharomyces cerevisiae. The exogenous substrate myelin basic protein was phosphorylated in all in vitro kinase assays containing copine III immunoprecipitate or purified copine III. A 60-kDa band was observed in corresponding in gel kinase assays with staurosporine-activated cells. Cell lines expressing high levels of copine III protein had correspondingly high kinase activity in copine III antiserum immunoprecipitate. However, the copine amino acid sequences lack the traditional kinase catalytic domain. Therefore, the data suggest copine III may possess an intrinsic kinase activity and represent a novel unconventional kinase family.

Expression of IL-2 receptor in dorsal root ganglion neurons and peripheral antinociception.

Interleukin-2 (IL-2), a T-cell growth factor, could exert an antinociceptive effect. Intraplantar injection of human recombinant IL-2 (rIL-2) at a dose of 10000/20 microl significantly enhanced pain threshold as measured by paw withdrawal latency (PWL) to noxious radiant heat in the rat. Reverse transcription modification of polymerase chain reaction (RT-PCR) analysis showed that IL-2R alpha and beta chains were constitutively expressed in rat dorsal root ganglion (DRG) neurons. Immunohistochemistry further demonstrated that IL-2R was mainly localized to small and medium-sized neurons, which are predominantly responsible for nociceptive transmission. These observations suggest that IL-2/IL-2R system may affect neural activities including nociceptive processing in DRG.

Quantitative flow cytometry to measure the TNF-alpha and IL-2 system after heart transplantation.

After heart transplantation a high incidence of infections and malignancies is found. Not only immunosuppression, but also intrinsic cytokine systems with some unbalance, e. g. TNF-alpha and IL-2, can result in impaired immune competence and may have a role in these complications. The aim of this study was to assess the activity of the TNF-alpha and IL-2 systems after heart transplantation. In peripheral blood we measured expression of activation markers of TNF-alpha (TNF-R2) and IL-2 (IL-2R alpha, IL-2R beta-chain) on monocytes and lymphocytes using quantitative flow-cytometric analysis. TNF-R2 expression was significantly enhanced on monocytes and lymphocytes in patients after heart transplantation, while the expression of IL-2R alpha and IL-2R beta was not elevated. Increased TNF-R2 expression in peripheral blood after heart transplantation reflects an activated TNF-alpha system, leading to high levels of active sTNF-R, which impairs TNF-alpha bioavailibility and consequently leads to immune incompetence.

Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors.

The importance of IL-2Rbeta function for immune regulation is highlighted by the severe impairment in lymphoid cell function in IL-2Rbeta-deficient mice. It has been speculated that failed IL-2/IL-2R signaling in peripheral T cells causes the associated autoimmunity, imbalanced peripheral lymphoid homeostasis, and defective T cell function. This study explored the requirement for IL-2Rbeta function in mature T lymphocytes. We show that transgenic thymic expression of the IL-2R beta-chain in IL-2Rbeta-deficient mice prevents lethal autoimmunity, restores normal production of B lymphocytes, and results in a peripheral T cell compartment that is responsive to triggering through the TCR, but not the IL-2R. The dysfunction of the IL-2R is illustrated by the near complete failure of mature T cells to proliferate to IL-2 in vitro and in vivo, to differentiate into CTL, and to up-regulate IL-2Ralpha expression. These data indicate that lymphoid homeostasis is largely maintained despite a nonfunctional IL-2R in mature T lymphocytes and suggest that IL-2Rbeta provides an essential signal during thymic development to regulate self-reactivity.

Association of STAT1, STAT3 and STAT5 proteins with the IL-2 receptor involves different subdomains of the IL-2 receptor beta chain.

Upon IL-2 stimulation of T lymphocytes, the IL-2 receptor (IL-2R) becomes phosphorylated on specific tyrosine residues which serve as docking sites for proteins containing SH2 or phosphotyrosine binding domains. To study the interaction of the IL-2Rbeta chain with Shc and STAT proteins, subdomains of the IL-2Rbeta chain were expressed as tyrosine-phosphorylated glutathione S-transferase fusion proteins and used to pull-down interacting proteins from Kit 225 cell lysates. These experiments provide direct biochemical evidence that binding to the IL-2R of the adaptor protein Shc requires phosphorylation of Tyr-338 in the IL-2Rbeta acidic subdomain. In addition, we report that STAT proteins that are activated by IL-2, i.e. STAT1, STAT3 and STAT5, indeed associate with the IL-2Rbeta chain. Both the A and B isoforms of STAT5 were found to associate with Tyr-510 of the IL-2Rbeta C-terminal region, depending on its phosphorylation. In contrast, STAT1 and STAT3 associated with the IL-2Rbeta chain through its acidic subdomain. These results indicate that the interaction between IL-2Rbeta and STAT1 or 3 does not require either phosphorylation of the receptor or even the presence of tyrosine residues of IL-2Rbeta. Thus, the IL-2R recruits STAT proteins through different modes of interaction.

Interleukin-2 induces cell cycle perturbations leading to cell growth inhibition and death in malignant mesothelioma cells in vitro.

Previous report indicated that Interleukin-2 (IL-2) is able to inhibit the growth of IL-2-receptor-positive cancer cell lines without any involvement of the immune system, through IL-2-induced alterations of the cell cycle kinetics. In this study we provide evidence that IL-2 exerts anti-proliferative effect on three human malignant mesothelioma (MMe) cells in vitro, while no effects were observed on normal human mesothelial cell (HMC) primary cultures. The growth inhibitory effect of IL-2 on neoplastic cells appeared to depend on the baseline proliferative status of these cells. Indeed, in highly proliferating MMe cells, we observed a reduction of malignant cells in the S-phase of the cell cycle, with an accumulation in G0/G1, followed by apotosis for longer incubations or exposure to higher doses. On the contrary, in MMe cells proliferating at lower rate, IL-2 induces only a late cytotoxic effect, leading to apoptosis, without significantly affecting the cell cycle. IL-2Rbeta mRNA was detectable by RT-PCR in all MMe cells, IL-2Ralpha mRNA in one only out the three assayed and IL-2Rgamma mRNA in none. In addition, mRNA specific for the IL-2Rbeta-associated Jak-1 tyrosine kinase was expressed in all MMe cell lines, further suggesting that IL-2Rbeta may play a role in the observed effects. Very low, albeit detectable, levels of IL-2Rbeta chain appeared to be expressed at the cell surface of MMe cells by indirect immunofluorescence and FACS analyses. Finally, Ca(++) fluxes were rapidly induced when MMe cells were exposed to exogenous IL-2.

RETRACTED: Uncoupling IL-2 Signals that Regulate T Cell Proliferation, Survival, and Fas-Mediated Activation-Induced Cell Death

IL-2 is an important growth and survival factor for T lymphocytes but also sensitizes these cells to Fas-mediated activation-induced cell death (AICD). The molecular basis of these different effects of IL-2 was studied by introducing wild-type and mutant forms of the IL-2 receptor beta (IL-2Rbeta) chain that lacked specific signaling capacities into receptor-deficient T cells by retroviral gene transfer. Activation of Stat5 by IL-2 was found to be involved in T cell proliferation and promoted Fas ligand (FasL) expression and AICD. T cell survival was dependent on a receptor region that activated Akt and the expression of Bcl-2. Thus, distinct IL-2Rbeta chain signaling modules regulate T cell fate by stimulating growth and survival or by promoting apoptosis.

Role of interleukin-2 receptor expression on macrophages from Salmonella-infected mice.

In this study, it was found that macrophages from Salmonella-infected mice expressed the interleukin-2 receptor (IL-2R). The IL-2R induced by the infection consisted mainly of both beta and gamma chains, and the expression of IL-2Ralpha was very low. Furthermore, similar expression of IL-2Rbeta and gamma chains was observed in interferon-gamma-treated macrophages. The effect of recombinant interleukin-2 on the intracellular killing activity of macrophages which expressed IL-2Rbeta and gamma was then studied. Our results demonstrated that interleukin-2 acted synergistically with interferon-gamma through the IL-2R in the induction of macrophage intracellular killing activity and established a new role of IL-2R on bactericidal activity of macrophages.

An IL-2 receptor beta subdomain that controls Bcl-X(L) expression and cell survival.

IL-2 binding to its high-affinity receptor regulates signaling events that control both lymphocyte cell survival and cell cycle progression. Although many studies have examined the mechanisms by which IL-2 regulates cell growth, few studies have dissected the pathways involved in promoting cell survival or the coupling of these pathways to the receptor. In the present study, using the pre-B cell line Baf-B03 transfected with a truncated form of the IL-2 receptor (IL-2R) beta chain, we demonstrate that IL-2-dependent cell survival requires only the N-terminal 350 amino acids of the IL-2Rbeta chain. IL-2-dependent survival of cells expressing the truncated receptor correlates with increases in receptor-associated phosphatidylinositol 3-kinase (PI3K) activity and expression of Bcl-X(L), but not with changes in c-Myc expression or proliferation. Inhibition of the PI3K pathway in these cells, but not in cells expressing the wild-type receptor, has a marked effect on the capacity of IL-2 to prevent cell death and diminishes the Bcl-X(L) response. The requirement for IL-2-induced PI3K activity in suppressing the onset of apoptotic cell death is discussed.