Role of T cells in the pathogenesis of Hodgkin's disease.
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B-Lymphocytes↗
Biomedical subjects
P Parronchi
Publications and source records attributed to P Parronchi.
Human bone marrow non-B, non-T cells produce interleukin 4 in response to cross-linkage of Fc epsilon and Fc gamma receptors.
Human bone marrow (BM) cells lacking T- and B-cell markers expressed RNA encoding interleukin (IL) 4 and secreted detectable amounts of IL-4 in supernatants in response to Fc epsilon or Fc gamma receptor (Fc epsilon R or Fc gamma R) cross-linking. In some experiments, IL-5 RNA expression in response to Fc epsilon R cross-linkage could also be detected. In contrast, RNA transcripts for, and secretion of, IL-2, IL-6, and interferon gamma were never observed. The presence of IL-3 in the cultures was essential for IL-4 production by non-B, non-T BM cells in response to Fc gamma R cross-linking and enhanced IL-4 RNA expression in response to Fc epsilon R cross-linking. Under the same experimental conditions, BM T and B lymphocytes, as well as peripheral blood T, B, and non-B, non-T cells, did not express IL-4 RNA. Prolonged incubation of non-B, non-T cells in IgE-free medium followed by extensive washing did not inhibit IL-4 production induced by anti-IgE antibodies, suggesting that the Fc epsilon R involved in the response has the characteristics of a high-affinity receptor. The Fc epsilon R+ cells were separated from the Fc epsilon R- cells by sorting non-B, non-T BM cell suspensions with fluorescein isothiocyanate-conjugated IgE and then assessed for both IL-4 RNA expression and alcian blue staining. Both IL-4-producing and alcian blue-positive cells segregated with the Fc epsilon R+ fraction. These data suggest that human BM cells, probably belonging to the mast cell and/or basophil lineage, are capable of producing IL-4 in response to Fc epsilon R or Fc gamma R cross-linkage.
Antigens, Differentiation↗
Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production.
We have established a large panel of T-cell clones (TCCs) specific for Dermatophagoides pteronyssinus and Lolium perenne group I grass pollen allergens (total, 61) and for tetanus toxoid and protein purified derivative bacterial antigens (total, 38) from the peripheral blood of two atopic individuals and then analyzed their ability to produce interleukin 4 (IL-4), IL-5, and interferon gamma (IFN-gamma). Upon stimulation with phorbol 12-myristate 13-acetate plus anti-CD3 antibody, the great majority of TCCs specific for bacterial components was able to produce both IL-4 and IFN-gamma, whereas most D. pteronyssinus- and L. perenne group I-specific TCCs produced IL-4, but no, or limited, IFN-gamma. Moreover, the mean amounts of IL-4 and IFN-gamma released by allergen-specific TCCs were significantly higher and lower, respectively, than the mean amounts produced by TCCs specific for bacterial components. Under the same experimental conditions, virtually all allergen-specific TCCs, but only one-third of tested TCCs specific for bacterial components, expressed IL-5 RNA and secreted IL-5 in their supernatants. Eighteen TCCs (nine specific for allergens and nine specific for bacterial components) were also assessed for their ability to induce IgE synthesis by autologous B cells in response to stimulation with the specific antigen. Under these experimental conditions, all allergen-specific TCCs, but only one-third of TCCs specific for bacterial components that produced IL-4 but no, or little, IFN-gamma induced the synthesis of detectable amounts of IgE. The demonstration that most allergen-specific helper T cells in atopic individuals are able to produce high amounts of IL-4 (and IL-5), but no IFN-gamma, may explain why allergens induce production of IgE antibodies and increase eosinophils.
Adult↗
In vitro infection with HIV enables human CD4+ T cell clones to induce noncognate contact-dependent polyclonal B cell activation.
Eleven (nine CD4+ and two CD8+) protein purified derivative-specific and eight tetanus toxoid-specific T cell clones (TCC), established from the peripheral blood of healthy persons, were cocultured in vitro with irradiated mononuclear cells from patients infected by HIV in the presence of PHA and polybrene. Two weeks post-HIV exposure, all 17 CD4+, but neither of the two CD8+, TCC exhibited integration of HIV in their genoma, as detected by polymerase chain reaction analysis, and released HIV into their supernatants, as detected by measuring both reverse transcriptase activity and p24 Ag. When co-cultured with either autologous or allogeneic B cells, all CD4+ HIV-infected TCC induced the synthesis of extraordinarily high amounts of IgM, IgG, and IgA. In contrast, their noninfected counterparts could provide helper function for Ig synthesis by autologous B cells only in the presence of the specific Ag (or anti-CD3 antibody), and induced allogeneic B cells to synthesize Ig only upon stimulation with anti-CD3 antibody. The supernatants of HIV-infected TCC failed to stimulate Ig synthesis in B cells. More importantly, when HIV-infected clonal T blasts and B cells were cultured in different chambers separated by a millipore membrane, permeable to molecules but not to cells, Ig synthesis did not occur. The Ig synthesis induced by HIV-infected TCC was also markedly inhibited by the addition in culture of either anti-CD4 or anti-LFA-1 antibody. In contrast, HIV-infected TCC maintained their ability to provide helper function for Ig synthesis in the absence of any stimulus, even after fixation with p-formaldehyde. These data demonstrate that in vitro infection with HIV enables human T cells to stimulate Ig synthesis by B cells by an Ag-nonspecific, MHC-unrestricted, contact-dependent mechanism. This may explain, at least in part, the hypergammaglobulinemia and other phenomena related to polyclonal B cell activation frequently seen in HIV-infected persons.
B-Lymphocytes↗
Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis.
A total number of 132 T cell clones (TCC) were obtained by PHA-stimulation of single T cells from mononuclear cell suspensions of conjunctival flogistic infiltrates of three patients with vernal conjunctivitis (VC). The phenotype and functional properties of these TCC were compared with those of 122 TCC contemporarily established from PB mononuclear cell suspensions of the same patients, 120 TCC established from lymph nodes of three patients with nonspecific hyperplastic lymphoadenitis and 159 TCC established from thyroid lymphocyte infiltrates of three patients with Graves' disease. The great majority of conjunctival TCC displayed the CD4+ CD8- phenotype (CD4/CD8 ratios ranging from 6.1 to 7.0), whereas the mean CD4/CD8 ratios for control TCC ranged from 0.9 to 2.4. After stimulation with either PHA or PMA plus anti-CD3 mAb, conjunctival TCC differed from control TCC for their ability to produce cytokines. In particular, a large number of conjunctival TCC produced IL-4, but no, or limited amounts of, IFN-gamma, whereas no difference was observed between conjunctival and control TCC with regard to the production of IL-2. The failure of IFN-gamma production by conjunctival TCC was apparently not caused by delay or block in cytokine production, but actually reflected the lack of IFN-gamma transcription. Virtually all conjunctival TCC able to produce IL-4, but not IFN-gamma, as well as most of those producing both cytokines, provided helper function for IgE synthesis in allogeneic normal B cells. The accumulation in the conjunctiva of patients with vernal conjunctivitis of CD4+ T cells that, apart from the production of IL-2, resembles murine Th2 cells for their profile of cytokine production and helper function suggests a possible role for these cells in the pathogenesis of the disease.
Adult↗
Cytokine production by allergen (Der pI)-specific CD4+ T cell clones derived from a patient with severe atopic disease.
Twenty-four T cell clones (TCC) specific for purified Dermatophagoides pteronyssinus group I allergen (Der p I) were established from the peripheral blood of a patient with severe atopic disease and assessed for cytokine production in response to stimulation with both phorbol 12-myristate 13-acetate and anti-CD3 monoclonal antibody. All Der p I-specific TCC produced high amounts of interleukin (IL)-4 in association with IL-3, IL-5 and granulocyte monocyte-colony stimulating factor (GM-CSF), whereas they produced variable amounts of IL-2 and virtually no interferon-gamma. These data support the hypothesis that atopy is associated with preferential activation of type 2 T helper cells and suggest a deregulation in the function of the IL-3, IL-4, IL-5 and GM-CSF gene cluster in subjects with severe atopic disorders.
Adult↗
Regulation of IgE synthesis by CD4+ human T-cell subsets.
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Allergens↗
The IgE response in atopy and infections.
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Humans↗
Lymphokine secretion and cytotoxic activity of human CD4+ T-cell clones against Bordetella pertussis.
Human CD4+ T-cell clones specific for pertussis toxin and other Bordetella pertussis antigens have been tested for their cytotoxic activity, lymphokine production, and capacity to induce immunoglobulin synthesis. Clones specific for the S1 subunit of pertussis toxin were cytotoxic for autologous Epstein-Barr virus-transformed B cells, which had been pulsed with the native antigen, the recombinant S1 subunit of pertussis toxin, or synthetic peptides derived from the S1 amino acid sequence. The killing of antigen-pulsed target cells was class II restricted. All of the T-cell clones produced mostly interleukin-2 and gamma interferon and assisted allogeneic B cells in the production of immunoglobulins M and G but not immunoglobulin E. The potential in vivo role of the cytotoxic activity of these clones is discussed.
B-Lymphocytes↗
Increased numbers of Th2-like CD4+ T cells in target organs and in the allergen-specific repertoire of allergic patients. Possible role of IL-4 produced by non-T cells.
Phytohemagglutinin (PHA)-induced human T cell clones (TCC) derived from conjunctival flogistic tissues of 3 patients with vernal conjunctivitis produced unusually high amounts of interleukin-4 (IL-4) and no, or limited amounts of, gamma-interferon (IFN-gamma). Allergen (Dermatophagoides pteronyssinus or Lolium perenne group I)-specific TCC derived from peripheral blood of two atopic donors produced significantly higher amounts of IL-4 and significantly lower amounts of IFN-gamma than TCC specific for bacterial antigens (tetanus toxoid and PPD) contemporarily established from the same donors. These data provide evidence for a compartimentalization of Th2-like helper T cells in target organs and in the allergen-specific T cell repertoire of allergic patients. Non-B, non-T bone marrow cells could produce IL-4, but not IL-2 or IFN-gamma, in response to cross-linkage of Fc epsilon type I receptors. These cells may further contribute to the maintenance and amplification of allergic inflammation.
Allergens↗
Noncognate contact-dependent B cell activation can promote IL-4-dependent in vitro human IgE synthesis.
We have previously shown that IL-4 is an essential mediator for the synthesis of human IgE in vitro. In this study we demonstrate that prior physical contact with T cells is required by B cells to synthesize IgE in response to IL-4. Both autologous and allogeneic freshly prepared T cells were consistently able to support IL-4-dependent IgE synthesis, provided that they were added to B cells together with, or before, the addition of IL-4. In addition, most CD4+, as well as a proportion of CD8+, PHA-induced T cell clones (TCC) established from two HLA-DR incompatible donors, supported, in the presence of exogenous IL-4, the synthesis of IgE in B cells from the majority of individuals tested including both donors of cloned T cells. An alloreactive TCC able to produce IL-4 in response to HLA-DR4+ B cells and to induce HLA-DR4+ B cells to synthesize IgE, acquired the ability to support IgE synthesis by B cells lacking the appropriate alloantigen provided that exogenous IL-4 was added. Although the ability of freshly prepared T cells to support IgE synthesis was consistently abrogated by fixation with paraformaldehyde (PF), such a treatment variably affected the IgE-inducing ability of TCC. Preactivation with anti-CD3 before treatment with PF maintained or even enhanced the ability of TCC to support IL-4-dependent IgE synthesis. More importantly, preactivation with anti-CD3, followed by fixation with PF, enabled TCC, apparently devoid of IgE-inducing activity in unfixed condition, to support IL-4-dependent IgE synthesis. Taken together these data suggest that at least two signals are involved in the triggering of human B cells to IgE production: the first is delivered by a T-B cell contact and the second by IL-4. The physical signal delivered by T cells does not necessarily consist of cognate interaction. Non-cognate contact-dependent induction of B cells to IgE synthesis in response to IL-4 appears to be related to molecule(s) distinct from the TCR/CD3 complex, but fully expressed on the membrane of TCR/CD3-activated T cells.
Antigens, Differentiation, T-Lymphocyte↗
The immune derangement and strategies for immunotherapy.
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Adult↗
Role of interleukins in induction and regulation of human IgE synthesis.
Studies of human IgE synthesis are summarized and provide further insight into the cellular and molecular mechanisms involved in IgE regulation, as well as in the alterations responsible for IgE disregulation in some pathological conditions. These include the demonstration that IL-4 is the essential factor for the induction of human IgE syntheses. Another T cell-derived lymphokine, IFN-gamma negatively regulated the IgE synthesis induced by IL-4. These two lymphokines can be produced by different T helper cells, as shown in mice, but they can also be the product of the same T cells clones. Additional cellular and/or molecular signals appear to be involved in the IL-4-induced IgE synthesis, but their precise role in this process is undetermined. Finally, alternations of one or more of these regulatory mechanisms can be detected in patients with pathological conditions characterized by hyperproduction of IgE. In particular, the increased prevalence of T cells clones able to produce IL-4 appears to be a distinctive feature of patients with common atopy whereas a reduction in the proportion of IFN-gamma-producing T cells seems to be peculiar of both patients with hyper-IgE syndrome and patients with AIDS.
Acquired Immunodeficiency Syndrome↗
Role of interleukin 4 and gamma interferon in the regulation of human IgE synthesis: possible alterations in atopic patients.
The IgE helper function of human T cell clones or their phytohemagglutinin-induced supernatants was positively correlated with their ability to produce or their content in interleukin 4 (IL-4), whereas it was inversely correlated with production of or content in gamma interferon. The addition to B cell cultures of anti-IL-4 antibody abolished not only the IgE synthesis induced by recombinant human IL-4, but also that induced by IL-4-producing T cell clones or their phytohemagglutinin-induced supernatants. A clonal analysis in nonatopic donors and patients with common atopy showed that atopics possess in their peripheral blood significantly higher numbers of T cells able to secrete IL-4 and to provide helper function for IgE.
CD4-Positive T-Lymphocytes↗
Defective in vitro production of gamma-interferon and tumor necrosis factor-alpha by circulating T cells from patients with the hyper-immunoglobulin E syndrome.
Circulating T cells from four patients with the hyper-IgE syndrome were found to produce significantly lower concentrations of interferon-gamma (IFN-gamma) in response to stimulation with phytohemagglutinin (PHA) than did T cells from eight age-matched healthy controls, three patients with atopic dermatitis and one patient with chronic granulomatous disease. A clonal analysis revealed that patients with hyper-IgE syndrome had markedly lower proportions of circulating T cells able to produce IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) in comparison with controls. In contrast, the proportions of peripheral blood T cells able to produce IL-4 or IL-2 were not significantly different in patients and controls. All the four patients with hyper-IgE syndrome showed high proportions of circulating CD4+ helper T cells able to induce IgE synthesis in allogeneic B cells, as well. Such an activity for IgE synthesis appeared to be positively correlated with IL-4 production by T cells and inversely related to the ability of the same T cells to produce IFN-gamma. Since IFN-gamma exerts an inhibitory effect on the synthesis of IgE and both IFN-gamma and TNF-alpha play an important role in inflammatory reactions, we suggest that the defective production of IFN-gamma may be responsible for hyperproduction of IgE and the combined defect of IFN-gamma and TNF-alpha may contribute to the undue susceptibility to infections seen in patients with hyper-IgE syndrome.
Adolescent↗
Role for T cells, IL-2 and IL-6 in the IL-4-dependent in vitro human IgE synthesis.
The role of T cells and monocytes, as well as that of cytokines, such as IL-1, IL-2 and IL-6, on the IL-4-dependent in vitro human IgE synthesis was investigated. Recombinant IL-4, IL-4-containing T-cell clone supernatants and different combinations of recombinant cytokines failed to induce highly purified B cells to synthesize IgE. IL-4-dependent IgE synthesis was restored by addition to purified B cells of either untreated or mitomycin C-treated autologous T lymphocytes. Addition to purified B cells of autologous monocytes did not restore the IgE response, but usually it exerted a potentiating effect on the synthesis of IgE induced by IL-4 in the presence of suboptimal concentrations of T cells. The activity of T cells apparently preceded that of IL-4 and required a physical contact with B cells. The presence in culture of IL-2 also appeared to be necessary for the T-cell and IL-4-dependent IgE synthesis. Even though not essential, IL-6 was able to potentiate IgE synthesis in most experiments, whereas IL-1 did not display any modulatory effect.
B-Lymphocytes↗
Regulatory mechanisms of in vitro human IgE synthesis.
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Biomechanical Phenomena↗
IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants.
The property of 109 CD4+ T cell clones (TCC) to induce IgE synthesis in vitro in human B cells was compared with their ability to produce IL-2, IL-4, and IFN-gamma in their supernatants (SUP) after 24-h stimulation with PHA. A significant positive correlation was found between the property of TCC to induce or enhance spontaneous IgE synthesis and their ability to release IL-4. In contrast, there was an inverse relationship between the IgE helper activity of TCC and their ability to release IFN-gamma, whereas no statistical correlation between the property to induce IgE synthesis and to produce IL-2 was observed. The ability of PHA-SUP from 71 CD4+ TCC to induce IgE synthesis in B cells was also investigated. Twenty-nine SUP (all derived from TCC active on IgE synthesis) induced production of substantial amounts of IgE in target B cells. There was a correlation between the amount of IgE synthesized by B cells in response to these SUP and their IL-4 content. An even higher correlation was found between the IgE synthesis induced by these SUP and the ratio between the amount of IL-4 and IFN-gamma present in the same SUP. Like IL-4-containing SUP, rIL-4 also showed the ability to induce IgE production in B cells from both atopic and nonatopic donors. The addition to B cell cultures of anti-IL-4 antibody virtually abolished not only the IgE synthesis induced by rIL-4, but also that stimulated by TCC and their SUP. In contrast, the IgG synthesis induced by TCC SUP was not or only slightly inhibited by the anti-IL-4 antibody. These data indicate that IL-4 is an essential mediator for the IgE synthesis induced in vitro by human TCC and their SUP in the absence of a polyclonal activator, whereas IFN-gamma seems to exert a negative regulatory effect on the production of IgE.
Adult↗