Biomedical subjects

I Höidén

Publications and source records attributed to I Höidén.

10 recordsLinked to original sources

PubMed1996

CD8+ cells are the main producers of IL10 and IFN gamma after superantigen stimulation.

Purified CD8+ T cells were recently shown to produce TH1 as well as TH2 types of cytokines upon restimulation, indicating an important role for these cells in regulation of immune responses. However, it is not known if the CD8+ cells would contribute to cytokine production in the presence of cytokine secreting CD4+ cells. In the present study the authors have investigated the proportion of cytokine-producing CD4+ and CD8+ cells in the spleen after in vitro or in vivo stimulation. They found that stimulation of spleen cells with the superantigen Staphylococcal Enterotoxin B (SEB) in the presence of IL4 promoted production of IL10 and IFN gamma predominately by CD8+ cells. In contrast, the production of IL4 was almost exclusively confined to the CD4+ subset. When priming with SEB in vivo before subsequent restimulation in vitro, a protocol previously shown to induce anergy, up to 80% of the IL10 and IFN gamma positive cell expressed the CD8 marker. Taken together, these results emphasize the important role of cytokine-producing CD8+ cells and indicate that CD4+ and CD8+ T cells may, in a given situation, produce distinct cytokines.

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PubMed1995

Superantigen-induced anergy in cytotoxic CD8+ T cells.

This study describes the use of bacterial superantigens to investigate the mechanisms governing peripheral tolerance in CD8+ T cells. Administration of superantigens to mice activates T cells to proliferation, cytokine production, and cytotoxicity, but responding cells subsequently enter a state of hyporesponsiveness or are deleted. Superantigen-induced inactivation has so far mainly been demonstrated for CD4+ T cells. Injection of amounts of the superantigen staphylococcal enterotoxin A (SEA) that are optimal for T cell activation and which induce anergy in CD4+ T cells result in preserved responsiveness in CD8+ CTLs. In contrast, we found that intravenous injection of low concentrations of SEA induced a profound down-regulation of the cytotoxic function in SEA-reactive CD8+ TCR V beta 11+ T cells. No reduction in the number of CD8+V beta 11+ T cells was found, suggesting that anergy and not deletion is the main mechanism for the observed cytotoxic hyporesponsiveness. The cytotoxic anergy was evident 2 days after low-dose priming and remained present 4 wk later, indicating a rapid induction phase and long-lasting persistence. The anergized CD8+ T cell subset expressed lower levels of the alpha-(CD11a) chain of the cell adhesion molecule lymphocyte function-associated Ag 1 (LFA-1) and failed to mediate cytotoxicity, but retained the capacity to proliferate, express IL-2R, produce IFN-gamma, and express granzyme mRNA, which imply a partial defect in TCR-transduced signals. Taken together, these findings suggest that there is a biphasic stimulus-dependent threshold for acquiring responsiveness or anergy in CD8+ T cells.

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PubMed1994

Superantigens anergize cytokine production but not cytotoxicity in vivo.

We have investigated the effect of the superantigen staphylococcal enterotoxin A (SEA) on the balance between T-cell response and non-responsiveness in T-cell receptor (TcR) V beta 3 transgenic mice. One injection of SEA resulted in a substantial activation of TcR V beta 3+ cells, whereas T cells from mice injected with repeated doses of SEA displayed a diminished response to a subsequent in vitro challenge. The reduced responsiveness became apparent when SEA was injected multiple times with short intervals. Proliferation and cytokine production in anergized T cells were severely reduced when stimulated with SEA in vitro, whereas cytotoxic T lymphocyte (CTL) activity remained unaffected. The dichotomy between these functions was examined in vitro with respect to different T-cell subsets. The total number of CD4+ T cells was reduced in the hyporesponsive spleens, compatible with cell deletion. The remaining CD4+ TcR V beta 3+ T cells showed anergy of all tested functions and did not respond to exogenous interleukin-2 (IL-2). In contrast, there was an expansion of CD8+ TcR V beta 3+ T cells with an intact cytotoxic activity. The in vitro proliferation and production of cytokines in the CD8+ compartment was impaired, but could be partially restored in the presence of exogenously added IL-2. Analysis of the cytokine response to SEA in vivo showed that IL-2 and tumour necrosis factor (TNF) were mainly produced by CD4+ T cells, while interferon-gamma (IFN-gamma) was predominantly released by CD8+ T cells. Induction of anergy resulted in a reduction of IL-2 and TNF mRNA levels, frequencies of producing cells as well as serum protein content. In contrast, there was only a moderate influence on the IFN-gamma level in vivo. The results suggest that SEA-induced hyporesponsiveness involves CD4+ cell deletion and a failure to produce cytokines in the remaining CD4+ T-cell compartment, while IFN-gamma production and cytotoxicity in the CD8+ T-cell compartment stay relatively intact.

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PubMed1993

Similar frequencies and kinetics of cytokine producing cells in murine peripheral blood and spleen. Cytokine detection by immunoassay and intracellular immunostaining.

Production of IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IFN-gamma, GM-CSF (granulocyte-macrophage colony stimulating factor) and macrophage colony stimulating factor by murine peripheral blood and spleen cells was analyzed following primary and secondary mitogen stimulation in vitro. Individual cytokine producing cells were detected by an intracytoplasmic staining technique. Cytokine production in cells from peripheral blood and spleen was comparable and more rapidly induced by calcium ionophore and phorbol 12-myristate 13-acetate than by concanavaling A. Restimulation in vitro induced both a swift production of cytokines and, for some cytokines, higher frequencies of producing cells. This was especially evident for IL-10 secreting cells, which increased 30-80 times in secondary responses. These analyses using the dual approaches of immunoenzymetric and fluorescent immunohistochemical techniques provide important evidence that cytokine induction kinetics can differ following primary or secondary stimulation.

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PubMed1993

Manipulation of the superantigen-induced lymphokine response. Selective induction of interleukin-10 or interferon-gamma synthesis in small resting CD4+ T cells.

The production of several lymphokines by freshly isolated CD4+ T cells has been analyzed at the single-cell level, after stimulation with staphylococcal enterotoxin B (SEB). High frequencies of cells producing interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) were induced, but very low frequencies of CD4+ T cells produced IL-4, IL-5 or IL-10 in response to SEB. Exogenously added IL-4 markedly altered the lymphokine profile induced during primary SEB stimulation. IFN-gamma production was reduced, while a high fraction of cells contained IL-10 and IL-4 after activation in the presence of IL-4. We further demonstrate that IL-4 and IL-10 or IFN-gamma production was selectively induced in resting, high-density CD4+ T cells during primary stimulation, by SEB + IL-4 or SEB. Under conditions where both IL-10 and IFN-gamma were produced, most cells contained only one of the two lymphokines.

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PubMed1993

Commitment to lymphokine profile during primary in vitro stimulation.

We have shown previously that different conditions in primary in vitro SEB stimulation of resting CD4+ T cells, could induce selectively production of either IFN gamma or IL4 and IL10. The present investigation shows that the priming conditions also decide which lymphokines will be produced during restimulations. The cells that had been induced to produce mainly IFN gamma during the primary SEB stimulation, or during stimulation with IL4 and IL10, synthesized the same lymphokines at restimulation, regardless of stimuli and were unaffected by exogenous IL4. Thus, at an early stage of primary SEB stimulation, cells became committed to produce a certain pattern of lymphokines which remained throughout the period of in vitro culture testing.

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PubMed1991

Interferon-gamma and growth factor production by murine T cells derived from three different lymphoid tissues.

Various antigen-presenting cells and the environment in different lymphoid tissues have been suggested to influence the type of lymphokine produced by T cells. We have investigated the mitogen-induced proliferation, interferon-gamma (IFN-gamma) and growth factor production by cells isolated from spleen, mesenteric and peripheral (axillary, brachial and inguinal) lymph nodes (LN). We found that stimulation with concanavalin A or staphylococcus enterotoxin B induced IFN-gamma synthesis in spleen cells but not in LN cells. Proliferation and growth factor production were comparable in the three cell populations. The addition of the phorbol ester phorbol 12-myristate 13-acetate (PMA), which is commonly used as a substitute for accessory cells, did not influence the IFN-gamma synthesis by LN cells. The growth factor production was, on the other hand, elevated by the addition of PMA. A high number of IFN-gamma-producing peripheral LN cells were obtained if they were stimulated in the presence of splenic adherent cells. The growth factor synthesis was marginally affected by the presence of these cells. Thus, splenic adherent cells provide a co-stimulatory signal to the T cell necessary for IFN-gamma synthesis.

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PubMed1991

The immunoglobulin receptors on B cells bind antigen, focus activation signals to them and initiate antigen-presentation.

We do not agree with the analysis of Langman and Cohn on the function of Ig receptors. We have reviewed the available literature regarding anti-Ig activation of B cells and found it contradictory and unconvincing. We have presented experimental evidence on the inability of Ig receptors on B cells to mediate activation or tolerogenic signals. We suggest that the Ig receptors serve to focus antigen to specific B cells so the B cells can be activated by TI antigens or helper T cells. The Ig molecules also bind foreign antigen and thereby initiate internalization and antigen processing. The processed peptides are exported to the membrane, where they associate with MHC class II antigens, thus transforming B cells into efficient antigen-presenting cells.

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PubMed1989

Capping and co-capping of membrane immunoglobulin and lipid-conjugated immunoglobulin inserted in the cell membrane of B lymphocytes.

Human and mouse immunoglobulins (Ig) or F(ab')2 fragments of rabbit Ig were conjugated to lipids and the conjugates inserted into the membrane of mouse spleen cells. It was found that nearly all B cells, but not T cells, became decorated with lipid immunoglobulin. Both endogenous Ig receptors and inserted Ig capped after the addition of cross-linking F(ab')2 antibodies and in both cases capping required energy. Capping of endogenous mouse Ig led to co-capping of inserted human Ig, but the reverse was not true.

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PubMed1989

Forced contact between antigen-presenting cells and T cells: consequences for T-cell activation.

It is still not known how T cells are activated, which T-cell surface structures transmit activation signals, and if antigen-presenting cells possess activation structures for T cells. We have studied whether the T-cell receptor (TcR) must be engaged for T-cell activation to occur. By using membrane-incorporated monoclonal antibodies, we artificially forced T cells to bind to antigen-presenting cells in a mixed lymphocyte reaction system and thereby bypassed the need for TcR engagement and also made it possible for any surface molecule on antigen-presenting cells to deliver a stimulatory signal to the T cells. Theoretically, T cells would become polyclonally activated by this procedure. However, we found that they did not, even though they were intimately bound to the antigen-presenting cell, thus demonstrating that the TcR must participate in antigen/MHC binding in order for the T cells to become activated. This study does not exclude the possibility that antigen-presenting cells possess structures that can activate T cells.

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