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PubMedDate not supplied

Characterization of thymic cell subpopulations involved in IL-1- or GM-CSF-induced IL-6 production.

IL-6 has been demonstrated by in vitro studies to be a cytokine involved in thymocyte activation We show herein that thymocytes cultured at high concentrations in the absence of comitogen respond to IL-1 and, to a lesser degree, to GM-CSF, by producing IL-6. This phenomenon disappears rapidly with decreasing cell densities, suggesting the involvement of a minor cellular component of the thymus which may be solely responsible for or cooperate in IL-6 production. We have analysed several thymic subpopulations for IL-6 production and show that accessory cells, and eventually their precursors, are the major if not exclusive, producers of this cytokine. Mature steroid-resistant thymocytes do not secrete IL-6. Production of IL-6 by total CD4-CD8- thymic cells is largely reduced by the depletion of mature accessory cells which express I-A and Mac-1 antigens. As shown previously, accessory cell precursors within the CD4-CD8- compartment are induced to differentiate into M phi and DC in response to IL-1 and GM-CSF. We provide evidence that this maturation is associated with IL-6 production. Thymic DC and phagocytic cells of the thymic reticulum (P-TR) in vitro produce high levels of IL-6 which are enhanced by GM-CSF or IL-1. These factors have a synergistic effect on IL-6 production by total thymocytes, and on CD4-CD8- cells that are not depleted for mature I-A+ Mac-1+ accessory cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Parallel regulation of IL-4 and IL-5 in human helminth infections.

To investigate the relationship between cytokine production and the increased levels of serum IgE and peripheral eosinophilia commonly accompanying human helminth infections, we studied the ability of PBMC of normal (N1) (n = 18) and eosinophilic individuals with helminth infections (H1) (n = 9) to produce IL-3, IL-4, IL-5, granulocyte-macrophage-CSF, and IFN-gamma in vitro after stimulation with PMA (50 ng/ml) and ionomycin (1 microgram/ml). The two groups differed in both the levels of serum IgE and eosinophilia. For mitogen-induced production of granulocyte-macrophage-CSF and IFN-gamma, there was no difference in cytokine production between the two groups. In marked contrast, supernatants from PBMC of infected individuals had significantly higher levels of IL-4 (mean = 213 pg/ml for N1 and 944 pg/ml for H1, p less than 0.02), IL-5 (mean = 180 pg/ml for N1 and 1118 pg/ml for HL, p less than 0.001), and IL-3 (mean = 13900 pg/ml for N1, 28029 pg/ml for H1, p less than 0.05). In addition, helminth-infected patients had approximately 5-fold greater numbers of T cells capable of producing IL-5 and 2.5-fold greater frequency of IL-4-secreting cells than did normal individuals; GM-CSF- and IFN-gamma-producing T cell numbers were not significantly different in the two groups. IL-3-producing cell frequencies could not be evaluated by this method. There was a direct correlation between IL-4 production and IL-5 production at the level of both protein production and frequency of T cells capable of producing these cytokines. These data indicate that individuals with reactive eosinophilia and elevated serum IgE have an expanded population of lymphocytes producing IL-4 and IL-5 and the association of the two suggests that the regulation of IL-4 and IL-5 may be linked.

CD4-Positive T-Lymphocytes↗
PubMed1992

Fibroblast stimulation in schistosomiasis. XII. Identification of CD4+ lymphocytes within schistosomal egg granulomas as a source of an apparently novel fibroblast growth factor (FsF-1).

Granulomas that form around Schistosoma mansoni eggs deposited in the liver secrete a variety of fibrogenic factors that may provide a molecular link between chronic inflammation and hepatic fibrogenesis in schistosomiasis. We recently isolated from conditioned medium of egg granuloma cultures a approximately equal to 60-kDa heparin-binding growth factor for fibroblasts. Because this protein is distinct from other defined heparin-binding growth factors, we designated it "fibroblast stimulating factor-1" (FsF-1). We now report that FsF-1 is a lymphokine. We prepared IgG antibody against purified FsF-1 and determined that it did not cross-react with a variety of growth factors or recombinant interleukins. Using two-color flow cytometry of dissociated granuloma cell suspensions, we observed that approximately 20% to 25% of granuloma CD4+ lymphocytes express surface FsF-1. We isolated CD4+ granuloma lymphocytes by FACS and observed that these cells spontaneously secrete into culture supernatant a fibroblast mitogen that is neutralized by anti-FsF-1 antibody. Furthermore, anti-FsF-1 can specifically immunoprecipitate a metabolically labeled protein produced by the granuloma CD4+ lymphocytes. The labeled protein has the same apparent molecular mass (approximately equal to 60 kDa) as FsF-1 purified from granuloma culture supernatants. These findings define CD4+ lymphocytes as a source of FsF-1. Because FsF-1 has biologic and chemical features distinct from most other defined lymphokines and from other heparin-binding growth factors, FsF-1 appears to be a novel lymphokine.

Animals↗
PubMed1992

Guidelines for the performance of CD4+ T-cell determinations in persons with human immunodeficiency virus infection.

This document has been developed by CDC to give guidance to laboratories performing lymphocyte immunophenotyping assays in human immunodeficiency virus-infected persons. The recommendations in this document reflect current technology in a field that is rapidly changing. The recommendations apply to laboratory safety, specimen collection, specimen transport, maintenance of specimen integrity, specimen processing, flow cytometer quality control, sample analyses, data analysis, data storage, data reporting, and quality assurance.

CD4-Positive T-Lymphocytes↗
PubMed1992

Helper T cell memory: more questions than answers.

The critical participation of helper T cells in immunologic memory of animals is clear. Features of antigen-specific CD4 memory cells in primed animals that distinguish them from naive cells are their increased frequency, their ability to secrete lymphokines in addition to IL-2 and their expression of distinct arrays of surface molecules. The latter include increased CD44, CD45RO, LFA-3 and VLA-4 and decreased CD45RA,B and Mel-14. These differences in surface markers may contribute to increased interaction potential for APC, and to distinct patterns of recirculation, but direct demonstrations of the former have yet to be provided. Other possible distinctions that are also largely hypothetical, include distinct requirements for activation and the ability to respond more rapidly to stimulation. The factors that regulate the development of memory helper T cells are also unknown.

Animals↗
PubMed1992

Progressive changes in CD45RB phenotype and lymphokine production by murine CD4+ T cells after alloantigen exposure.

Changes in CD45R expression correlate with changes in phenotype in mouse, rat and human T cells. It has been shown in mouse that CD45RB high T cells produce mostly interleukin-2 (IL-2) while CD45RB low T cells produce more IL-4 than IL-2 after mitogen stimulation in vitro. CD45RB expression also decreases when T cells are stimulated. In this study we compared responses of CD45RB high and low CD4+ T cells to alloantigens. Although a majority of unstimulated murine T cells from unimmunized mice are CD45RB high, we were able to isolate and purify sufficient numbers of T cells to study their response to alloantigens. When separated cells were stimulated in vitro with alloantigen the CD45RB high T cells became heterogeneous for their expression of CD45RB, indicating that high cells decrease their expression of CD45RB epitopes. Surprisingly, only CD45RB high T cells from unimmunized mice were alloreactive, as measured by proliferation and lymphokine secretion. In contrast, both CD45RB high and low populations from mice primed with allogeneic spleen were responsive to alloantigens. The 'primary' response of T cells from alloantigen-primed mice to third party stimulators is 10-fold greater in the CD45RB high population than in the CD45RB low, as would be predicted by our results in the primary mixed lymphocyte/leucocyte reaction (MLR). Furthermore, the response of CD45RB low T cells from unprimed mice and the response to third party alloantigen from primed mice was reconstituted by the addition of exogenous IL-2. The response of CD45RB low cells from primed mice was specific, as the third party alloresponsive cells were again primarily contained within the CD45RB high population. In the CD45RB high population in the secondary MLR we observed an increase in the production of IL-4 relative to IL-2.

Animals↗
PubMed1992

The role of T cells in pathogenesis and protective immunity to murine malaria.

T-cell-mediated immunity to a virulent strain of Plasmodium berghei NK65 (Pb NK65) and to an attenuated derivative (Pb XAT) of the strain were examined in CBA mice by the administration of monoclonal antibodies against T-cell subsets or interferon-gamma (IFN-gamma). The injection of anti-CD8+ or anti-IFN-gamma delayed the mortality of mice infected with Pb NK65, although it did not affect the parasitaemia. In the late stage of PB NK65 infection, T cells, especially CD8+ T cells, were increased in number in the liver at the expense of splenic CD8+ T cells. These CD8+ T cells released IFN-gamma in culture without antigen stimulation and were thought to induce tumour necrosis factor-alpha (TNF-alpha) production by the cells in the liver. In mice infected with Pb XAT, or mice primed with Pb XAT and then challenged with Pb NK65, CD4+ T cells had a crucial role in preventing parasite growth and in protective immunity. IFN-gamma was again the key molecule in protective immunity. These results suggest that T cells stimulated with malaria antigen play important roles both in protective immunity and pathogenesis depending upon their subsets; CD8+ T cells in pathogenesis, and CD4+ T cells in protective immunity. These apparently contradictory responses may be mediated by the same cytokine, IFN-gamma.

Animals↗
PubMed1992

IgG subclass responses to Theiler's murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains.

Inbred mouse strains differ in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. A strong correlation between disease susceptibility and delayed-type hypersensitivity (DTH) has been previously demonstrated, but no strong correlation between disease susceptibility and total anti-TMEV ELISA titres was shown. Since both DTH and IgG2a antibody production are regulated by CD4+ Th1 cells, we investigated three strains of mice to determine whether antivirus IgG2a antibody levels, like DTH in previous studies, correlated with disease susceptibility. Susceptible SJL/J, intermediately susceptible C3H/HeJ, and resistant C57BL/6 mice were infected intracerebrally (i.c.) with the BeAn strain of TMEV and monitored for clinical signs of demyelination and for levels of TMEV-specific antibody of different IgG subclasses using a particle concentration fluorescence immunoassay (PCFIA). Resistant C57BL/6 mice were found to have significantly lower concentrations of total anti-TMEV antibody than susceptible SJL/J mice and intermediately susceptible C3H/HeJ mice show variable antibody responses. A predominance of anti-TMEV IgG2a (Th1 regulated) antibody was seen in susceptible and intermediately susceptible mice, whereas resistant mice displayed a predominant anti-TMEV IgG1 (Th2 regulated) response accompanied by a marked deficiency of IgG2a. In contrast, immunization of C57BL/6 mice with UV-inactivated TMEV in adjuvant revealed that this strain was not defective either in its ability to generate high levels of anti-TMEV antibody or in its ability to produce IgG2a antibody. These results suggest that the antivirus IgG subclass profile is dependent upon the immunization route, virus viability and/or the use of adjuvant and that the levels of antivirus subclasses may be predictive of disease susceptibility.

Animals↗
PubMed1992

The relationship of HIV-1 viral sequences detected by the polymerase chain reaction in haemophilic patients to clinical and other markers of infection.

A nested primer polymerase chain reaction (PCR) of pol gene sequences of human immunodeficiency virus-1 (HIV-1) was applied to whole blood of 31 haemophiliacs who were, or had been, positive for HIV p24 antibody (HIVAb) by enzyme linked immunosorbent assay (ELISA) and samples from 22 persistently HIVAb negative haemophiliacs who had been at risk of contracting HIV from treatment. The results were compared with those of p24 HIV antigen determination, T4 cell counts beta 2 Microglobulin (beta 2M) levels and clinical evidence of progression of HIV disease. There was no discrepancy between the PCR results and past or present seropositivity for HIVAb. The qualitative PCR was more sensitive than the p24 antigen assay but the presence of the latter was predictive of progression of infection as determined clinically and by falling T4 cell counts and rising levels of beta 2M. The results of the PCR are reassuring for HIVAb negative haemophiliacs at risk from treatment and to HIVAb negative sexual contacts of HIVAb positive persons.

Adult↗
PubMed1992

Generation of B cell memory and affinity maturation. Induction with Th1 and Th2 T cell clones.

We used an adoptive transfer system and CD4+ T cell clones with defined lymphokine profiles to examine the role of CD4+ T cells and the types of lymphokines involved in the development of B cell memory and affinity maturation. Keyhole limpet hemocyanin (KLH)-specific CD4+ Th2 clones (which produce IL-4 and IL-5 but not IL-2 or IFN-gamma) were capable of inducing B cell memory and affinity maturation, after transfer into nude mice or after transfer with unprimed B cells into irradiated recipients and immunization with TNP-KLH. In addition, KLH-specific Th1 clones, which produce IL-2 and IFN-gamma but not IL-4 or IL-5, were also effective in inducing B cell memory and high affinity anti-TNP-specific antibody. The induction of affinity maturation by Th1 clones occurred in the absence of IL-4, as anti-IL-4 mAb had no effect on the affinity of the response whereas anti-IFN-gamma mAb completely blocked the response. Th1 clones induced predominantly IgG2a and IgG3 antibody, although Th2 clones induced predominantly IgG1 and IgE antibody. We thus demonstrated that some Th1 as well as some Th2 clones can function in vivo to induce Ig synthesis. These results also suggest that a single type of T cell with a restricted lymphokine profile can induce both the terminal differentiation of B cells into antibody secreting cells as well as induce B cell memory and affinity maturation. Moreover, these results suggest that B cell memory and affinity maturation can occur either in the presence of Th2 clones secreting IL-4 but not IFN-gamma, or alternatively in the presence of Th1 clones secreting IFN-gamma but not IL-4.

Animals↗
PubMed1992

Production of transmembrane and secreted forms of tumor necrosis factor (TNF)-alpha by HIV-1-specific CD4+ cytolytic T lymphocyte clones. Evidence for a TNF-alpha-independent cytolytic mechanism.

Candidate AIDS vaccines consisting of recombinant forms of the HIV-1 envelope glycoprotein induce, in seronegative human volunteers, an env-specific T cell response that includes CD4+, MHC class II-restricted CTL capable of lysing HIV-1-infected target cells. In this study, we have analyzed the production of the cytokines TNF-alpha and lymphotoxin (LT) by a set of env-specific CD4+ human CTL clones. TNF-alpha and LT are of interest because of their potential role in target cell destruction by CD4+ CTL. Our studies focused on the possibility that a cell surface form of TNF-alpha expressed by CTL after physiologic activation with target APC might participate in the cytolytic reactions mediated by these clones. We found that, upon interaction with target cells expressing env epitopes in the context of the appropriate MHC class II molecules, CD4+ CTL released TNF-alpha with kinetics that were rapid, compared with other cytokines, and that were generally similar to the kinetics of target cell destruction. LT secretion was not detected during the time course of the cytolytic reactions. A novel flow cytometric assay was used to show that physiologic activation of CD4+ CTL with target APC induced expression by the CTL of cell surface forms of TNF-alpha. Immunoprecipitations from activated, surface-iodinated CTL clones revealed two forms of surface TNF-alpha, a 26-kDa form, representing the transmembrane precursor of secreted TNF-alpha, as well as the 17-kDa secreted form bound to the cell surface. For a subset of CD4+ CTL, we found that treatment of CTL with cyclosporin A inhibited Ag-induced production of both transmembrane and secreted forms of TNF-alpha but had no effect on cytolysis. Thus, although transmembrane and secreted TNF-alpha produced by HIV-1-specific CD4+ CTL may have important effects in vivo, the rapid destruction of target APC by the set of CD4+ CTL clones described here occurs through a TNF-alpha-independent mechanism.

Antigen-Presenting Cells↗
PubMed1992

Reduced susceptibility to HIV-1 infection of ethyl-methanesulfonate-treated CEM subclones correlates with a blockade in their protein kinase C signaling pathway.

We have described the isolation of chemically induced CEM subclones that express CD4 receptors and bind soluble gp120, yet show a markedly reduced susceptibility to infection with HIV-1. Two subclones were found to have an abnormal response to the protein kinase C (PKC) activator PMA. PMA treatment induced CD3 and CD25 (IL-2R) receptors on the parental line and on other ethyl-methanesulfonate-derived subclones, but not on these two mutants. Direct assays of PKC activity were conducted. Total cellular PKC enzymatic activity was found to be normal in these subclones. PMA-induced CD4 down-modulation occurred normally. In addition, activation of c-raf kinase was normal. Since HIV-1 long terminal repeat contains two functional nuclear factor kB (NF-kB) regulatory elements, we studied the ability of PMA to induce NF-kB binding activity by different assays. Chloramphenicol acetyl transferase (CAT) assays using the HIV-1 (-139)long terminal repeat-CAT construct showed no PMA induction of CAT activity in these subclones (unlike the parental line and other subclones). Okadaic acid, an inhibitor of phosphatases 1 and 2A, did not overcome the defect in these subclones. Gel retardation assays, using a 32P-probe containing the HIV-1 NF-kB probe and nuclear extracts from PMA-treated cells, showed significantly reduced induction of nuclear NF-kB binding proteins in these two subclones compared with wild type CEM and a control subclone. Deoxycholate treatment of cytoplasmic extracts from these subclones released much reduced NF-kB binding proteins from their cytoplasmic pools. Thus, reduced levels of PKC-induced nuclear NF-kB activity in two T cell subclones did not affect their normal cell growth, but correlated with a pronounced reduction in their susceptibility to HIV-1 infection.

Base Sequence↗
PubMed1992

CD45 alternative exon expression in murine and human CD4+ T cell subsets.

Leukocytes express a family of high m.w. glycoproteins called leukocyte common Ag (CD45), which are involved in phosphotyrosine signal transduction. Antibodies to different CD45 isoforms distinguish functionally different CD4+ T cell subsets in humans, rats, and mice. Selected protein isoforms are expressed through a process of exon splicing that is cell-type and differentiation-state specific. Splicing of the three variable exons, A, B, and C, which encode amino acids located near the extracellular amino terminus of the protein, potentially results in generation of eight different mRNA transcripts. The purpose of the present study was to determine the relative levels of all eight different CD45 transcripts present in a panel of murine CD4+ T cell lines and normal murine and human CD4+ T cell subsets separated with antibodies to CD45 variable exons. We show, as expected, that the broad features of CD45 surface isoform expression in these cells can be accounted for by the relative amounts of the eight differentially spliced transcripts. Unexpectedly, all the differences in CD45 isoform expression among the CD4+ T cell subpopulations that we measured could be accounted for by differences in the overall level of variable exon expression. We did not see differences among T cell populations in the relative expression of particular variable exons. Exon B was always found in greater abundance than exons C or A. Of the dual exon species, only AB and BC were found in CD4+ T cells. The AC species was undetectable. Human CD4+ T cells, especially those in the naive subset, express higher levels of CD45 variable exons than murine CD4+ T cells.

Animals↗
PubMed1992

Role of CD4+ (helper) T cells in the pathogenesis of murine cytomegalovirus myocarditis.

Murine cytomegalovirus causes diffuse myocardial lesions in immunologically intact young adult male BALB/cBy mice. The cardiac changes develop in and around the small penetrating blood vessels of the heart where perivascular and interstitial infiltrates of macrophages and lymphocytes accumulate. Focal lesions of the coronary vessels and the endocardium also appear. When infected mice are depleted of CD4+ T lymphocytes, myocardial lesions fail to develop even though virus replication in the heart is enhanced. Contrary wise, when CD4+ cells are adoptively transferred into infected, thymectomized, irradiated, bone marrow-repleted mice, focal perivascular necrotizing lesions of the heart develop. Depletion of CD8+ T lymphocytes fails to influence virus replication and the development of cardiac lesions. Endothelial and endocardial cells appear to be major sites of virus replication in the heart. Delayed hypersensitivity is hypothesized to be the mechanism of cardiac injury in this model system.

Animals↗
PubMedDate not supplied

[Epidemiological surveillance of infection by the human immunodeficiency virus (HIV) and of the acquired immunodeficiency syndrome (AIDS) in French Polynesia in 1991].

The authors make out a statement about HIV infection in French Polynesia at the date of 1991 December 31. 96 cases all together of seropositive and AIDS infected people were recorded. These patients are young generally (78 p.c. between 21 and 40 years old) sexually contaminated (72 out of 96) and live in Tahiti island (94 p.c.). Sex-ratio is 2.8 male/1 female. Among them, we noted 55 p.c. of Europeans, 38 p.c. of Polynesians and 7 p.c. of Asiatic people. Epidemiological monitoring of the infection was made easy because of a set of laws and possibilities of detection highly favourable. Progress of the infection is constant, with 20 new cases detected each year with a prevalence of 150 cases of AIDS per 1 million of inhabitants, French Polynesia could be classified as the 5th or 6th region of France as far as the importance of the disease. Clinical, biological and epidemiological taking of charge of patients is detailed as well as the prevention campaign.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Heart allografts in murine systems. The differential activation of Th2-like effector cells in peripheral tolerance.

Activated CD4+ Th2 cells release cytokines (IL-4,-10) that block activation & cytokine (IL-2/IFN-gamma) release by proinflammatory T (CD4+,CD8+) effector cells. To test the hypothesis that peripheral tolerance to alloantigen is linked to differential activation of CD4+ Th2 cells we measured cytokine transcripts in heart grafts (C57BL/10----C3H/HeJ) and spleens of mice rendered "tolerant" by donor-specific blood transfusion, anti-CD4 mAb pretreatment, and cyclosporine administration. The expression of IL-2/IFN-gamma transcripts was reduced greater than 90% in grafts from tolerant recipients. IL-4/IL-10 transcripts were generally enhanced and persisted in graft and recipient spleen. Accordingly adoptive transfer studies were performed to determine whether Th2-like effectors, which express Fc receptors (FcR), mediate suppression in this model. Unfractionated mononuclear cells (MC) (5 x 10(6), isolated from spleens of heart graft recipients made tolerant by DST, prolonged the survival of test grafts greater than 90 days in irradiated (680 rads) recipients reconstituted with a sufficient number of MC from spleens of naive C3H to precipitate rejection of the test graft in 18.2 days (MST, n = 5). Conversely adoptive transfer of inocula depleted of FcR+ cells on immune complex columns or with anti-FcR mAb 24G2 caused test grafts to be rejected in 8-11 days. These results suggest that peripheral tolerance to alloantigen may be linked to differential activation of Th2 cells that induce anergy by suppression. The possibility that Th2-like effectors mediate peripheral tolerance to self is discussed.

Animals↗
PubMed1992

Herpetic stromal keratitis: an immunopathologic disease mediated by CD4+ T lymphocytes.

To investigate the role of T cell subsets in the development of herpetic stromal keratitis (HSK) in a well defined model, we used an adoptive transfer approach in which thymectomized and T cell-depleted mice [T(-)] were reconstituted with different numbers of syngeneic immune T lymphocytes after topical corneal challenge with RE strain of herpes simplex virus-1. In vitro stimulated or unstimulated immune T cells obtained from cervical and retropharyngeal lymph nodes of mice with HSK were used in adoptive transfer experiments. Although T(-) mice developed an initial epithelial inflammation, stromal keratitis did not occur. Reconstitution experiments revealed that mice that received 2 x 10(7) or more unfractionated immune T cells could develop HSK lesions with severity comparable to immuno-competent control mice. In mice receiving CD8(+)-depleted populations, even fewer cells (5 x 10(6)/mouse) were able to induce significant HSK. In contrast, mice that received similar or increased numbers of cells depleted of CD4+ T lymphocytes did not develop HSK. Immune T lymphocytes transferred to mice that were mock infected on the cornea did not develop HSK, indicating that the immunopathogenic cells were virus specific and not merely reacting to autoantigens. Histopathologic examination of the diseased corneas demonstrated that the stromal inflammation in euthymic normal and T(-)-reconstituted mice was characterized by extensive polymorphonuclear leukocyte infiltration. Scattered lymphocytes, and occasional macrophages also were observed. These results provide further evidence that HSK represents an immunopathologic process mediated mainly by CD4+ T cells.

Animals↗