Two distinct factors are required for induction of T-cell growth

Larsson, Eva‐Lotta; Iscove, Norman N.; Coutinho, António

doi:10.1038/283664a0

Cited by 397 publications

(103 citation statements)

References 15 publications

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“…Recently, several other investigators (15)(16)(17)(18)(19) have demonstrated a requirement for the macrophage product, interleukin 1 (IL-1), in the production of IL-2 by murine lymphocytes. Moreover, Maizel et al (20) reported that human monocyte-produced IL-1 augments lectin-stimulated mitogenesis of human T cells purified from peripheral blood.…”

Section: Resultsmentioning

confidence: 99%

Prostaglandin E inhibits the production of human interleukin 2.

Rappaport¹,

Dodge²

1982

The Journal of Experimental Medicine

381

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A substantial body of evidence implicates prostaglandins (PG) as potent local regulators of the immune response (1, 2). Inhibition of human T cell proliferation by PG of the E type (PGE) is well established (3), but the mechanism is poorly understood. The discovery of interleukin 2 (IL-2), the lymphokine required for T cell proliferation (4, 5), has permitted further elucidation of this inhibitory event. Previously, it was shown (6, 7) that exogenous PGE inhibited lymphokine production by guinea pig lymph node lymphocytes, and recently it was reported (8) that PGE suppressed IL-2 production by murine lymphocytes. We report here that PGE inhibits the production of IL-2 by normal human peripheral blood lymphocytes, whereas PG of the type F (PGF) or A (PGA) do not. Further, we found that PG synthetase inhibitors raised IL-2 above normal levels. Removal of glass-adherent cells from mononuclear cell populations also led to increased IL-2 production by nonadherent cells. These cells were less responsive to stimulation by PG synthetase inhibitors but remained sensitive to inhibition by PGE. The results indicate that PGE, secreted by an adherent cell population, regulates the production of IL-2. Materials and MethodsSeparation of Lymphocytes. Peripheral venous blood, drawn from normal fasting men and women into heparinized Vacutainer tubes (Beeton Dickinson & Co., Rutherford, N J) was centrifuged at 1,200 g for 4 rain to reduce volume and achieve partial separation of cells. After removal of plasma, the white cell layer was recovered and diluted with an equal volume of Hanks' balanced salt solution (HBSS). Mononuclear cells were isolated by Ficoll-Paque (Pharmacia Fine Chemicals, Div. of Pharmacia Inc., Piscataway, N J) density gradient centrifugation. The resultant lymphocyte-rich bands (unfractionated lymphocytes) were washed three times in HBSS and suspended in Hepes-huffered RPMI 1640 medium (M. A. Bioproducts, Walkersville, MD) containing 100 #g/ml streptomycin, 100 U/ml penicillin, 2.5 #g/ml Fungizone, and 5 × 10 -n M 2-mercaptoethanol (complete medium). Cell viability was >90% as determined by the trypan blue exclusion method. In some experiments, the blood was first passed through two successive glass wool columns (Pyrex wool; Coming Glass Works, Coming, NY) (600 g/10-cc syringe) to remove adherent cells. This adherent cell-depleted suspension is referred to as the nonadherent mononuclear cell population.Production of IL-2. Unfractionated or nonadherent mononuclear cells were cultivated at a concentration of 10 e cells/ml in complete medium supplemented with 2% heat-inactivated human AB serum. Cultures containing 1 #g/ml phytohemagglutinin (PHA) (Wellcome Reagents, Ltd., Beekenharn, England) were incubated in the presence and absence of various compounds (PG, indomethacin or fentiazac) for 48 h at 37°C in a humidified atmosphere of 5% COs. After incubation, culture supernatants (conditioned medium [CM]) were sterilized by

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Section: Resultsmentioning

confidence: 99%

Prostaglandin E inhibits the production of human interleukin 2.

Rappaport¹,

Dodge²

1982

The Journal of Experimental Medicine

381

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“…IL-1 constitutes a second signal for T cell activation provided by APC carrying the first signal, i.e. MHC class II molecules [6][7][8]. In vitro, IL-1 upregulates the activity of T helper cells, possibly influencing the balance between different subsets [2,9].…”

Section: Introductionmentioning

confidence: 99%

In vitro activation of antigen-presenting cells (APC) by defined composition of Quillaja saponaria Molina triterpenoids

Behboudi

Morein

Villacrés-Eriksson

1996

Clinical and Experimental Immunology

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SUMMARYThe capacity of adjuvants to stimulate cytokine production by APC is important for the initiation of the immune response. Novel adjuvant formulations based on the iscom technology have been developed using selected triterpenoid components from Quillaja saponaria Molina. Five of these new Quillaja formulations were used to prepare matrix (an antigen-free particle) and tested for their capacity to stimulate IL-1 secretion by murine peritoneal cells in vitro. The formulation denominated QH 7.0.3 was superior to the other matrix formulations, including the original spikoside matrix. The QH 7.0.3 formulation in iscoms containing influenza virus envelope antigens induced IL-1 secretion more efficiently than the antigen-free matrix, or a mixture of matrix and viral antigens, or the free Quillaja components of similar composition. Compared with adjuvants known as IL-1 inducers, QH 7.0.3 fluiscoms were as efficient as the most prominent IL-1 inducer, i.e. lipopolysaccaride (LPS) and superior to cholera toxin (CT) and muramyl dipeptide (MDP). These results indicate that the composition per se of triterpenoids included in iscoms or matrix has a prominent influence on the level of APC activation which may result in qualitatively different immune responses in vivo.

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“…Initially, antigen interacts with the T-cell antigen receptor, which leads to the transition from Go to GI and the expression of interleukin 2 (IL-2) receptor and lymphokines including IL-2. Further GI progression requires additional signals provided by the interaction of IL-2 with its high-affinity receptor, which results in the expression of genes related to G, activation, and binding of prolactin to its receptor, which results in entry into S phase and DNA replication (11,14,35,38,67).…”

mentioning

confidence: 99%

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

Huang¹,

Shipman-Appasamy²,

Orten³

et al. 1994

Mol. Cell. Biol.

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The proliferating-cell nuclear antigen (PCNA) gene encodes an auxiliary factor of DNA polymerase delta and functions in DNA replication during S phase. It is expressed at much higher levels in proliferating cells than in quiescent cells. We have studied the regulatory role of the 5'-flanking sequence of the murine PCNA gene in interleukin 2 (IL-2)-responsive cloned T cells (L2). Analysis of a set of deletion constructs in transient transfection assays measuring heterologous reporter gene (luciferase) activity demonstrated that the 182-bp 5'-flanking region provides full promoter activity in IL-2-stimulated L2 cells. While many elements contribute to PCNA promoter strength in IL-2-stimulated cells, the largest decrease in activity occurred with deletion of the tandem CRE (cyclic AMP response element) binding sites located at nucleotides -37 to -52. With a gel mobility shift assay, several IL-2-inducible DNA-protein complexes were detected, including CREB (CREbinding) and ATFI (activating transcription factor) proteins that are specific for the PCNA-CRE sequence.Methylation interference analysis confirmed specific binding of these proteins to the CRE sites. Mutation at the PCNA-CRE motif abolishes IL-2-inducible binding and reduces substantially PCNA promoter activity.These results indicate that IL-2-stimulated PCNA transcription may be partially mediated by these CRE-binding proteins.The activation of antigen-specific T lymphocytes from Go to S phase usually requires several signals. Initially, antigen interacts with the T-cell antigen receptor, which leads to the transition from Go to GI and the expression of interleukin 2 (IL-2) receptor and lymphokines including IL-2. Further GI progression requires additional signals provided by the interaction of IL-2 with its high-affinity receptor, which results in the expression of genes related to G, activation, and binding of prolactin to its receptor, which results in entry into S phase and DNA replication (11,14,35,38,67).One of the genes expressed during IL-2-driven G, progression is proliferating-cell nuclear antigen (PCNA) (49, 69). PCNA was originally described as a proliferation-associated nuclear antigen that was thought to be expressed in a cellcycle-specific manner (8,47). While PCNA is an auxiliary protein for DNA polymerase delta (leading-strand polymerase) (9, 59) and PCNA-associated immunofluorescence closely parallels [3H]thymidine incorporation during cell cycle progression (42), synthesis and expression of PCNA can be detected in all phases of the cell cycle (G11SG2/M) in proliferating cells, suggesting that the protein is easily extractable when it is not associated with the polymerase (10, 49). Beach and coworkers showed recently that D-type cyclins can directly interact with PCNA and suggested this interaction as one possible mechanism by which the cell cycle machinery could * Corresponding author. Present address:

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Two distinct factors are required for induction of T-cell growth

Cited by 397 publications

References 15 publications

Prostaglandin E inhibits the production of human interleukin 2.

Prostaglandin E inhibits the production of human interleukin 2.

In vitro activation of antigen-presenting cells (APC) by defined composition of Quillaja saponaria Molina triterpenoids

Promoter activity of the proliferating-cell nuclear antigen gene is associated with inducible CRE-binding proteins in interleukin 2-stimulated T lymphocytes.

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