scholarly journals Two Distinct Pathways of Interleukin-5 Synthesis in Allergen-Specific Human T-Cell Clones Are Suppressed by Glucocorticoids

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2891-2900 ◽  
Author(s):  
Akio Mori ◽  
Osamu Kaminuma ◽  
Matsunobu Suko ◽  
Satoshi Inoue ◽  
Takeo Ohmura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Segment ◽  
Allergic Diseases ◽  
Coding Region ◽  
Mobility Shift ◽  
T Cell Clones ◽  
Interleukin 5 ◽  
Human T Cell ◽  
Cell Clones

Abstract Glucocorticoids (GC) have long been used as the most effective agents for the treatment of allergic diseases accompanied by eosinophilia such as chronic asthma and atopic dermatitis. The development of chronic eosinophilic inflammation is dependent on interleukin-5 (IL-5), a selective eosinophil-activating factor, produced by helper T cells. To delineate the regulatory mechanisms of human IL-5 synthesis, we established allergen-specific CD4+ T-cell clones from asthmatic patients. GC efficiently suppressed IL-5 synthesis of T-cell clones activated via either T-cell receptor (TCR) or IL-2 receptor (IL-2R). Induction of IL-5 mRNA upon TCR and IL-2R stimulation was totally inhibited by dexamethasone. Human IL-5 promoter/enhancer-luciferase gene construct transfected to T-cell clones was transcribed on either TCR or IL-2R stimulation and was clearly downregulated by dexamethasone, indicating that the approximately 500-bp human IL-5 gene segment located 5′ upstream of the coding region contains activation-inducible enhancer elements responsible for the regulation by GC. Electrophoretic mobility shift assay analysis suggested that AP-1 and NF-κB are among the possible targets of GC actions on TCR-stimulated T cells. NF-AT and NF-κB were not significantly induced by IL-2 stimulation. Our results showing that GC suppressed IL-5 production by human CD4+ T cells activated by two distinct stimuli, TCR and IL-2R stimulation, underscore the efficacy of GC in the treatment of allergic diseases via suppression of T-cell IL-5 synthesis.

scholarly journals Public and private human T-cell clones respond differentially to HCMV antigen when boosted by CD3 copotentiation

2020 ◽  
Vol 4 (21) ◽  
pp. 5343-5356
Author(s):  
Laura R. E. Becher ◽  
Wendy K. Nevala ◽  
Shari Lee Sutor ◽  
Megan Abergel ◽  
Michele M. Hoffmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clonal Expansion ◽  
Antigen Receptors ◽  
Fab Fragment ◽  
Public And Private ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
Human T Cells

Abstract Human cytomegalovirus (HCMV) induces long-lasting T-cell immune responses that control but do not clear infection. Typical responses involve private T-cell clones, expressing T-cell antigen receptors (TCRs) unique to a person, and public T-cell clones with identical TCRs active in different people. Here, we report the development of a pretherapeutic immunostimulation modality against HCMV for human T cells, CD3 copotentiation, and the clonal analysis of its effects in recall assays at single-cell resolution. CD3 copotentiation of human T cells required identification of an intrinsically inert anti-CD3 Fab fragment that conditionally augmented signaling only when TCR was coengaged with antigen. When applied in recall assays, CD3 copotentiation enhanced the expansion of both public and private T-cell clones responding to autologous HLA-A2(+) antigen-presenting cells and immunodominant NLVPMVATV (NLV) peptide from HCMV pp65 protein. Interestingly, public vs private TCR expression was associated with distinct clonal expansion signatures in response to recall stimulus. This implied that besides possible differences in their generation and selection in an immune response, public and private T cells may respond differently to pharmacoimmunomodulation. Furthermore, a third clonal expansion profile was observed upon CD3 copotentiation of T-cell clones from HLA-A2(−) donors and 1 HLA-A2(+) presumed-uninfected donor, where NLV was of low intrinsic potency. We conclude that human T-cell copotentiation can increase the expansion of different classes of T-cell clones responding to recall antigens of different strengths, and this may be exploitable for therapeutic development against chronic, persistent infections such as HCMV.

scholarly journals Variable Immortalizing Potential and Frequent Virus Latency in Blood-Derived T-Cell Clones Infected With Human T-Cell Leukemia Virus Type I

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3303-3314 ◽  
Author(s):  
J.H. Richardson ◽  
P. Höllsberg ◽  
A. Windhagen ◽  
L.A. Child ◽  
D.A. Hafler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Leukemia Virus ◽  
Type I ◽  
Cell Leukemia Virus Type ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
T Cell Leukemia Virus ◽  
Spontaneous Proliferation

Abstract Human T-cell leukemia virus type I (HTLV-I)-infected T cells expanded in vitro by single-cell cloning provide a unique system for investigating virus-cell interactions in nonimmortalized T cells. By analysis of clones generated randomly from the blood of virus carriers, we confirm that CD4 T cells are the major reservoir of HTLV-I in vivo and show that most infected cells contain a single integrated provirus. Contrary to the situation in HTLV-I immortalized cell lines, the HTLV-I provirus was found to be transcriptionally silent in a high proportion of randomly generated T-cell clones and could not be reactivated by mitogenic stimulation. The spontaneous proliferation previously documented in HTLV-I–infected T-cell clones was not observed in silently infected cells, and therefore correlates directly with the expression of tax and other viral genes. The only cytokine mRNA found to be significantly elevated in the virus-producing clones was interleukin-6; however, receptor-blocking experiments argue against a role for IL-6 in the virus-induced cell proliferation. We observed a striking variation in the ability of individual HTLV-I–producing clones to immortalize fresh peripheral blood lymphocytes. This ability did not correlate with the levels of viral mRNA expression, gag p24 production, spontaneous proliferation, or tax-transactivation, possibly suggesting a role for host cell factors as determinants of viral infectivity or immortalization. Studies to elucidate the basis of this phenotypic heterogeneity should enhance our understanding of viral spread and pathogenesis.

scholarly journals Lymphokine regulation of CD45R expression on human T cell clones.

1989 ◽  
Vol 170 (6) ◽  
pp. 2147-2152 ◽  
Author(s):  
S A Brod ◽  
C E Rudd ◽  
M Purvee ◽  
D A Hafler
Keyword(s):  
Molecular Weight ◽  
T Cells ◽  
T Cell ◽  
Activated T Cells ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
Human T Cells ◽  
Single Cell Cloning ◽  
Cell Expression

Whether the expression of higher molecular weight isoforms of the T-200 complex represents different lineages of T cells and/or a sequential stage of the differential pathway of T cells has been unclear. Understanding T cell expression of higher molecular weight isoforms of the T-200 complex (CD45R) may be important because of their association with regulation of immune responses. By direct single cell cloning, we observed a number of long-term T cell clones that expressed CD45RA (2H4). CD45RA expression could be further regulated by ionomycin or the cytokines IL-1 and IL-6, but not IL-2, IL-4, or IFN-gamma. These results indicate that CD45RA expression may define T cell lineages of activated T cells partially controlled by the cytokines IL-1 and IL-6. Further, these results may associate regulatory actions of IL-1 and IL-6 with their ability to increase CD45RA expression in subpopulations of human T cells.

scholarly journals Transformation of human T-cell clones by Herpesvirus saimiri: intact antigen recognition by autonomously growing myelin basic protein-specific T cells

1993 ◽  
Vol 90 (23) ◽  
pp. 11049-11053 ◽  
Author(s):  
F Weber ◽  
E Meinl ◽  
K Drexler ◽  
A Czlonkowska ◽  
S Huber ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
Myelin Basic Protein ◽  
Interferon Gamma ◽  
Basic Protein ◽  
Herpesvirus Saimiri ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones

Herpesvirus saimiri has recently been shown to immortalize human T cells. It was unknown, however, whether Herpesvirus saimiri transformation affects T-cell receptor (TCR) expression and signal transduction. In the present study, we have transformed CD4+ human T-cell clones specific for human myelin basic protein. The transformed T cells were grown in interleukin 2 and divided in the absence of antigen and antigen-presenting cells. They retained the membrane phenotype of activated T cells and secreted the cytokines interferon gamma and lymphotoxin, but interleukin 4 was not detected. Further, the transformed T cells continued to express the original TCR as demonstrated by TCR variable-region-V beta-specific monoclonal antibodies and TCR sequencing. Antigen-specific recognition and signal transduction by the TCR were demonstrated by myelin-basic-protein-induced HLA-DR-restricted secretion of interferon gamma and lymphotoxin and by myelin-basic-protein-specific proliferation. Antigen specificity and reactivity have been maintained for > 1 year after transformation. Transformation with Herpesvirus saimiri now allows the production of virtually unlimited numbers of (auto)antigen-specific T cells expressing functional TCR and a stable membrane phenotype. This technology will facilitate studies of the pathogenesis of putative autoimmune diseases, such as multiple sclerosis, and may be of help in TCR-targeted immunotherapy.

Histamine Affects Interleukin-4, Interleukin-5, and Interferon- γ Production by Human T Cell Clones from the Airways and Blood

1998 ◽  
Vol 18 (5) ◽  
pp. 721-730 ◽  
Author(s):  
Frans H. Krouwels ◽  
Bernard E. A. Hol ◽  
René Lutter ◽  
Ben Bruinier ◽  
Aalt Bast ◽  
...  
Keyword(s):  
T Cell ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
T Cell Clones ◽  
Interleukin 5 ◽  
Human T Cell ◽  
Cell Clones

scholarly journals Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones.

1994 ◽  
Vol 179 (1) ◽  
pp. 279-290 ◽  
Author(s):  
K W Wucherpfennig ◽  
A Sette ◽  
S Southwood ◽  
C Oseroff ◽  
M Matsui ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Peptide Binding ◽  
Peptide Epitope ◽  
T Cell Clones ◽  
High Affinity ◽  
Human T Cell ◽  
Cell Clones

Immunodominant T cell epitopes of myelin basic protein (MBP) may be target antigens for major histocompatibility complex class II-restricted, autoreactive T cells in multiple sclerosis (MS). Since susceptibility to MS is associated with the DR2 haplotype, the binding and presentation of the immunodominant MBP(84-102) peptide by DR2 antigens were examined. The immunodominant MBP(84-102) peptide was found to bind with high affinity to DRB1*1501 and DRB5*0101 molecules of the disease-associated DR2 haplotype. Overlapping but distinct peptide segments were critical for binding to these molecules; hydrophobic residues (Val189 and Phe92) in the MBP(88-95) segment were critical for peptide binding to DRB1*1501 molecules, whereas hydrophobic and charged residues (Phe92, Lys93) in the MBP(89-101/102) sequence contributed to DRB5*0101 binding. The different registers for peptide binding made different peptide side chains available for interaction with the T cell receptor. Although the peptide was bound with high affinity by both DRB1 and DRB5 molecules, only DRB1 (DRB1*1501 and 1602) but not DRB5 molecules served as restriction elements for a panel of T cell clones generated from two MS patients suggesting that the complex of MBP(84-102) and DRB1 molecules is more immunogenic for MBP reactive T cells. The minimal MBP peptide epitope for several T cell clones and the residues important for binding to DRB1*1501 molecules and for T cell stimulation have been defined.

scholarly journals Vβ1+ Jβ1.1+/Vα2+ Jα49+ CD4+ T Cells Mediate Resistance against Infection with Blastomyces dermatitidis

2006 ◽  
Vol 75 (1) ◽  
pp. 193-200 ◽  
Author(s):  
Marcel Wüthrich ◽  
Hanna I. Filutowicz ◽  
Holly L. Allen ◽  
George S. Deepe ◽  
Bruce S. Klein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Blastomyces Dermatitidis ◽  
T Cell Clones ◽  
Interleukin 5 ◽  
Protective Antigens ◽  
Cell Clones ◽  
A Cell ◽  
Ifn Γ

ABSTRACT Immunization with a cell wall/membrane (CW/M) and yeast cytosol extract (YCE) crude antigen from Blastomyces dermatitidis confers T-cell-mediated resistance against lethal experimental infection in mice. We isolated and characterized T cells that recognize components of these protective antigens and mediate protection. CD4+ T-cell clones elicited with CW/M antigen adoptively transferred protective immunity when they expressed a Vα2+ Jα49+/Vβ1+ Jβ1.1+ heterodimeric T-cell receptor (TCR) and produced high levels of gamma interferon (IFN-γ). In contrast, Vβ8.1/8.2+ CD4+ T-cell clones that were reactive against CW/M and YCE antigens and produced little or no IFN-γ either failed to mediate protection or exacerbated the infection depending on the level of interleukin-5 expression. Thus, the outgrowth of protective T-cell clones against immunodominant antigens of B. dermatitidis is biased by a combination of the TCR repertoire and Th1 cytokine production.

scholarly journals Characterization of Human CD4+ T-Cell Clones Recognizing Conserved and Variable Epitopes of the Lassa Virus Nucleoprotein

2000 ◽  
Vol 74 (5) ◽  
pp. 2186-2192 ◽  
Author(s):  
Jan ter Meulen ◽  
Marlis Badusche ◽  
Kristiane Kuhnt ◽  
Andrea Doetze ◽  
Judith Satoguina ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Amino Acid Sequences ◽  
Eastern Africa ◽  
Proliferation Index ◽  
Lassa Virus ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones

ABSTRACT T cells must play the major role in controlling acute human Lassa virus infection, because patients recover from acute Lassa fever in the absence of a measurable neutralizing antibody response. T cells alone seem to protect animals from a lethal Lassa virus challenge, because after experimental vaccination no neutralizing antibodies are detectable. In order to study human T-cell reactivity to single Lassa virus proteins, the nucleoprotein (NP) of Lassa virus, strain Josiah, was cloned, expressed in Escherichia coli, and affinity purified. Peripheral blood mononuclear cells (PBMC) obtained from 8 of 13 healthy, Lassa virus antibody-positive individuals living in the Republic of Guinea, western Africa, were found to proliferate in response to the recombinant protein (proliferation index ≥10). PBMC obtained from one individual with a particularly high proliferative response were used to generate 50 NP-specific T-cell clones (TCC). For six of these the epitopes were mapped with overlapping synthetic peptides derived from the sequence of the NP. These CD4+TCC displayed high specific proliferation and produced mainly gamma interferon upon stimulation with NP. Because variation of up to 15% in the amino acid sequences of the structural proteins of naturally occurring Lassa virus variants has been observed, the reactivity of the TCC with peptides derived from the homologous epitopes of the Nigeria strain of Lassa virus and of the eastern Africa arenavirus Mopeia was tested. With the Nigeria strain of Lassa virus the levels of homology were 100% for two of these epitopes and 85% for three of them, whereas homology with the respective Mopeia epitopes ranged from 92 to 69%. Reactivity of the TCC with peptides derived from the variable epitopes of the Nigeria strain and of Mopeia was reduced or completely abolished. This report shows for the first time that seropositive individuals from areas of endemicity have very strong memory CD4+ T-cell responses against the NP of Lassa virus, which are partly strain specific and partly cross-reactive with other Lassa virus strains. Our findings may have important implications for the strategy of designing recombinant vaccines against this mainly T-cell-controlled human arenavirus infection.

scholarly journals Human T cells cannot act as autonomous antigen-presenting cells, but induce tolerance in antigen-specific and alloreactive responder cells.

1992 ◽  
Vol 176 (3) ◽  
pp. 875-880 ◽  
Author(s):  
S Sidhu ◽  
S Deacock ◽  
V Bal ◽  
J R Batchelor ◽  
G Lombardi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Clone ◽  
Antigen Presenting Cells ◽  
Accessory Cell ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
T Cell Clone ◽  
Antigen Presenting

The ability of two HLA-DR-expressing human T cell clones to function as antigen-presenting cells (APC) was investigated using highly purified T cells. The results demonstrated that these T cell clones are unable to act as autonomous APC, and that recognition of nominal or alloantigens on the surface of T cells leads to a state of nonresponsiveness. The first observation was that a T cell clone with specificity for the 306-324 peptide of influenza hemagglutinin (HA), and raised from a DR1 responder, exhibited apparent degeneracy of major histocompatibility complex restriction when cultured with peptide in the presence of peripheral blood mononuclear cells (PBMC) expressing a wide variety of structurally unrelated DR types. However, when the PBMC were pulsed with peptide and washed before coculture with the clone, peptide was exclusively recognized with DR1Dw1. This implied that in the presence of soluble peptide the T cells were displaying ligand to each other, and that the third-party APC were providing costimulatory signals. To test the ability of T cells to act as autonomous APC, accessory cell-free preparations of two DR1-restricted clones were cultured with peptide in the presence or the absence of added B cell APC. T cell purity was established by the absence of proliferation in response to the mitogen phytohemagglutinin (PHA). PHA-nonresponsive T cells were completely unable to proliferate in response to peptide alone; furthermore, preculture of the HA-specific clone, in the complete absence of accessory cells, with the same concentration of peptide (1 microgram/ml) that induced optimal proliferation when presented by conventional APC, led to profound nonresponsiveness. The same phenomenon was also observed when two of three anti-DR1 alloreactive T cell clones were precultured with a DR1-expressing T cell clone. The ability of the DR1-expressing clone to induce nonresponsiveness in anti-DR1 clones correlated with recognition of the DR1 alloantigen on the DR1-expressing clone.

scholarly journals Lineages of human T-cell clones, including T helper 17/T helper 1 cells, isolated at different stages of anti–factor VIII immune responses

Blood ◽  
2009 ◽  
Vol 114 (7) ◽  
pp. 1423-1428 ◽  
Author(s):  
Ruth A. Ettinger ◽  
Eddie A. James ◽  
William W. Kwok ◽  
Arthur R. Thompson ◽  
Kathleen P. Pratt
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Factor Viii ◽  
Hemophilia A ◽  
T Helper ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
Polarized Cells

AbstractThe development of neutralizing antibodies (inhibitors) after factor VIII (FVIII) infusions is a serious complication that affects approximately one-quarter of hemophilia A patients who have access to replacement therapy. To investigate the differentiation of naive T cells into FVIII-specific helper T cells that promote B-cell activation and antibody secretion, HLA-DRA-DRB1*0101-restricted T-cell clones that respond to a specific epitope in FVIII were isolated from a mild hemophilia A subject (the proband) 19 weeks and 21 months after his development of a high-titer inhibitor. Clones responding to the same epitope were also isolated from his multiply infused brother, who has not developed a clinically significant inhibitor. The 19-week proband clones were T helper (TH)17/TH1- or TH1/TH2-polarized, whereas all 8 clones isolated 21 months postinhibitor development were TH2-polarized cells. In contrast, all 6 clones from the brother who did not develop an inhibitor were TH1-polarized, indicating that tolerance to FVIII can be maintained even with circulating TH1-polarized cells that respond vigorously to in vitro FVIII stimulation. This is the first evidence that TH17/TH1-polarized cells play a role in hemophilic immune responses to FVIII. Furthermore, this is the first report of successful isolation and expansion of antigen-specific human TH17/TH1 clones using standard culture conditions.

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