IL6 and the T-cell response (original) (raw)
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European Journal of Immunology, 1990
Accessory factors involved in murine T cell activation. Distinct roles of interleukin 6, interleukin 1 and tumor necrosis factor Interleukin (IL) 6 was compared to other macrophage-derived products for its capacity to support the proliferation of accessory cell-depleted T cells. Monoclonal anti-IL 6 antibodies were found to inhibit completely the "accessory activity" of macrophage supernatants, thus demonstrating the central role played by IL6 inTcell activation. IL6 was apparently more critical for initiating than in maintaining T cell proliferation because anti-IL 6 antibodies lost all inhibitory activity when added late to the culture. Moreover, IL6 was not the only accessory factor required for optimal T cell proliferation. Using low-density cultures to minimize the number of contaminating accessory cells, we found that significant proliferation of CD4 cells was obtained only in the presence of both IL 6 and IL 1. In contrast ,with CD8 cells substantial proliferation was obtained with IL6 alone. This response could, however, be enhanced by IL 1. Tumor necrosis factor (TNF) and granulocyte/macrophage colony-stimulating factor showed no activity in these assays. The concentrations of IL 1 and of IL 6 required to support optimal proliferation were 10 pg/ml and 1 ng/ml, respectively. Analysis of the mechanisms underlyingTcell activation by IL 1 and IL 6 indicated that both cytokines were required for optimal production of IL2 but that IL6 alone was sufficient to confer IL2 responsiveness. For CD8 cells, this effect was observed with doses of IL6 about 100 times lower than those required for the induction of IL2 secretion (0.001 vs. 0.1 ng/ml). TNF, which was not capable of inducing IL2 secretion, was also found to induce IL2 responsiveness but only at a concentration 2 : lo00 times higher than that of IL6. In accordance with these observations, IL6 and to a lesser extent TNF were found to enhance IL2R expression by CD8 cells. Interestingly, this enhancing effect was totally dependent on the presence of IL2.
Cytokine, 2001
Functional roles of interleukin (IL-)6 in T cell response were investigated. Mice deficient in IL-6 and wild mice were immunized with antigens (myelin oligodendrocyte glycoprotein or methylated BSA) and production of IL-4 and interferon (IFN)-gamma by regional lymph nodes was measured. IL-6 deficiency led to an enhancement of IL-4 and an inhibition of IFN-gamma production. Moreover, polyclonal stimulation of spleen T cells from unimmunized IL-6-deficient mice with anti-CD3 plus anti-CD28 antibodies (Abs) demonstrated an enhancement of T helper (Th)(2)responses. The presence of IL-6, however, augmented IL-4 production but it inhibited IFN-gamma expression by spleen T cells in response to polyclonal stimulation and by antigen-primed spleen T cells in response to re-challenge with the antigen. In contrast, the induction of spleen CD4-positive T cells into Th(2)cells in vitro by the anti-CD3 plus IL-4 was completely suppressed by exogenously added IL-6, whereas Th(1)differentiation of T cells by the anti-CD3 plus IL-12 was not inhibited by the presence of IL-6. Thus, these results indicate that IL-6 physiologically could modulate qualitative T cell response and suggest that it augments Th(1)responses partly through its inhibitory capability of IL-4-induced Th(2)differentiation of naive T cells.
Blood, 1990
Two monocyte-derived cytokines, interleukin-1 (IL-1) and interleukin-6 (IL-6), have been reported to costimulate monocyte-depleted T cell populations in the presence of mitogen, and this effect has been attributed to an accessory function of these molecules. We have now examined further the accessory function potential of IL-1 plus IL-6, and examined how these cytokines promote T cell growth with mitogen. Together, IL-1 and IL-6 additively and, to a small degree, synergistically promote the proliferation of highly purified human peripheral blood T cells with phytohemagglutinin (PHA). However, maximum costimulation by IL-1 plus IL-6 over a wide range of concentrations is significantly smaller than that induced by optimal numbers of monocytes. Also, in contrast to monocytes that costimulate equally effectively T4 positive and T8 positive cells, IL-1 plus IL-6 costimulate T4 positive lymphocytes in marked preference to T8 positive cells. IL-1 plus IL-6 induces IL-2 secretion in T cell ...
Cellular Immunology, 1991
It has been documented that interleukin-6 (IL-6) supports the proliferation of purified, anti-CD3stimulated murine T cells. We found that stimulation of human peripheral blood mononuclear cells (PBMCs) with anti-CD3 induced a significant accumulation of IL-6 mRNA, indicating that antigen-mediated T-cell activation may involve IL-6 release from accessory cells. Phytohemagglutinin (PHA) had little effect upon IL-6 gene expression. In keeping with these findings. anti-IL-6 reduced but did not abolish anti-CD3-mediated proliferation of PBMCs, but had no significant effect upon PHA-stimulated proliferation. The addition of recombinant (r) IL-6 enhanced the proliferation of anti-CD3-stimulated PBMCs and increased the accumulation of IL-2 mRNA in PHA-stimulated PBMCs during the first 5 hr of culture. Nuclear run-off experiments did not reveal significant changes in IL-2 transcription in PHA plus rIL-6-treated PBMCs attempting to assume that IL-6 mediates stabilization of IL-2 mRNA. However, monitoring of partially spliced IL-2 mRNA by polymerase chain reaction revealed a clear increase in IL-2 heteronuclear RNA. Thus IL-6 increases the rate of IL-2 transcription which was not detectable by conventional in vitro transcription assays. We conclude that anti-CD3 triggers T-cell proliferation through a process that is partially but not entirely dependent upon release of IL-6. IL-6. in turn, supports IL-2 transcription. Insofar as anti-CD3 mimicks antigen-triggered activation of the T-cell receptor complex, IL-6 appears to support the early immune response by augmenting antigen-triggered IL-2 gene eXpr&OII.
European Journal of Clinical Investigation, 2008
Within 15 min, approximately 2 3 % of '"Ilabelled interleukin-6 (IL-6) injected intravenously into rats was taken up by the spleen. As determined by light microscopic autoradiography, uptake was mainly (60'%) accounted for by macrophages in the red pulp. "51-IL-6 binding in rat peritoneal macrophages was quantitatively similar to that in cultured human monocytes and T-cells. By comparison, IL-6 binding to polymorphonuclear granulocytes and freshly isolated monocytes was low. Stimulation with antigen, but not with mitogen (PWM), induced receptor presentation in B-cells, whereas antigen and mitogen downregulated the binding in T-cells. At 4 C, labelled IL-6 bound to cells with a half-time of about 1.5 h. Binding appeared reversible, but dissociation was slow and incomplete. The apparent K d for IL-6 binding was about 30 pmol I-' in most cell types, however, values of approximately 120 pmol I-' were obtained in polymorphonuclear granulocytes. At 37'C, '251-IL-6 was rapidly internalized by T-cells and monocyte-macrophages, and after a lag time, TCAsoluble radioactivity was released from the cells following a sigmoidal curve. Polyacrylamide gel electrophoresis of radiolabelled IL-6 cross-linked to its binding sites in T-cells, yielded receptor-ligand complexes with molar masses of 70-80 and 120-140 kg mol-I. This would agree with a dimeric conformation of the IL-6 receptor.
Role of IL-6 in the commitment of T cell subsets
Cytokine, 2021
IL-6 gained much attention with the discovery that this cytokine is a non-redundant differentiation factor for Th17 cells and T follicular helper cells. Adaptive immune responses to fungi and extracellular bacteria are impaired in the absence of IL-6. IL-6 is also required for the induction of ROR-γt + Treg cells, which are gatekeepers of homeostasis in the gut lamina propria in the presence of commensal bacteria. Conversely, severe immunopathology in T cell-mediated autoimmunity is mediated by Th17 cells that rely on IL-6 for their generation and maintenance. Recently, it has been discovered that the differentiation of these distinct T helper cell subsets may be linked to distinct signaling modalities of IL-6. Here, we summarize the current knowledge on the mode of action of IL-6 in the differentiation and maintenance of T cell subsets and propose that a contextdependent understanding of the impact of IL-6 on T cell subsets might inform rational IL-6-directed interventions in autoimmunity and chronic inflammation.
Immunology, 2002
T helper 2 (Th2) cytokines [interleukin (IL)-4 and IL-5] play a central role in the development of allergic immune responses. After allergen provocation, the expression of Th2 cytokines is rapidly up-regulated in atopy and asthma. IL-6 is a multifunctional cytokine that is able to direct Th2 immune responses and is secreted by multiple tissue cell types. This study shows that IL-6 induces up-regulation of IL-4 and IL-5 after short (5 min) preincubation periods in freshly isolated, a-CD3/ a-CD28-stimulated T cells. After longer preincubation periods with IL-6 (12 and 24 hr), the priming effect on IL-4 production gradually disappears, whereas the effect on IL-5 becomes more pronounced. In contrast, a small but significant inhibitory effect is found on the production of the Th1 cytokine interferon-g. Additional experiments indicate that the long-term priming effect of IL-6 on IL-5 production is dependent on IL-2 signalling. This is not the case for the short-term IL-6 effect on IL-5 secretion, where the p38 mitogen-activated protein kinase-dependent induction of activator protein-1 DNA-binding activity is involved, independent of signal transducer and activator of transcription 3 phosphorylation. In summary, these data demonstrate that the short-term and long-term priming effects of IL-6 on Th2 cytokine production are regulated by different mechanisms.
Proceedings of The National Academy of Sciences, 1988
Recombinant human interleukin 6 (IL-6), also termed B-cell-stimulatory factor 2 (BSF-2) or interferon-.32, was found to stimulate the proliferation of mouse thymocytes costimulated with phytohemagglutinin (PHA). In addition, IL-6 synergistically enhanced the stimulation of thymocyte proliferation by recombinant human interleukin 1 (IL-1) or interleukin 2 (IL-2). Mature thymocytes lacking peanut agglutinin receptor are the main target of IL-6 action. Incubation of thymocytes with IL-6 in the presence of PHA resulted in an increased expression of the IL-2 receptor (IL-2R) as demonstrated by flow cytometry. Monoclonal antibody specific for the p55 chain of the murine IL-2R significantly reduced IL-6-stimulated thymocyte proliferation in the presence of the optimal concentration of PHA. However, the same monoclonal antibody failed to reduce IL-6-driven thymocyte proliferation in the presence of a suboptimal PHA concentration, suggesting that IL-6 stimulates thymocyte proliferation by way of IL-2-dependent and IL-2-independent pathways. These results indicate that, in addition to its earlier demonstrated ability to promote B-cell differentiation and growth, IL-6 also acts as a growth regulator in cells of the T-lymphocyte lineage. IL-6 is emerging as an important regulatory cytokine with multiple actions on immune functions.