scholarly journals Antigen-specific suppressor T cell interactions. II. Characterization of two different types of suppressor T cell factors specific for L-glutamic acid50-L-tyrosine50 (GT) and L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT).

1983 ◽  
Vol 158 (6) ◽  
pp. 1962-1978 ◽  
Author(s):  
J A Kapp ◽  
C M Sorensen ◽  
C W Pierce
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Indirect Evidence ◽  
Target Cells ◽  
Antigen Binding ◽  
Complete Suppression ◽  
Antigen Binding Site ◽  
Suppressor Factor ◽  
Suppressor T Cell ◽  
Single Polypeptide Chain

We have previously reported that two types of suppressor T cell factors (TsF) specific for L-glutamic acid50-L-tyrosine50 (GT) or L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) can be distinguished based upon differences in their ability to suppress responses by allogeneic mice. Injection of GAT or GT induces a suppressor T cell subset that produces an antigen-binding, I-J+, genetically unrestricted, specific suppressor factor (TsF1). Injection of this factor plus small amounts of antigen induces a second-order suppressor T cell that produces an antigen-binding, I-J+, genetically restricted, specific suppressor factor (TsF2). In this report, we demonstrate that these two factors are also biochemically distinct. Monoclonal TsF1 molecules are composed of a single polypeptide chain that bears both the antigen-binding site and I-J determinant, whereas TsF2 molecules are composed of two disulfide-linked polypeptide chains, one of which is antigen-binding and I-J-, and the other, nonantigen-binding, I-J+. The antigen-binding chain must be added at culture initiation to achieve suppression, but the I-J+ chain can be added as late as day 3 with complete suppression observed. However, isolated chains from TsF2-producing hybridomas derived from three different haplotypes were unable to suppress immune responses when chains from heterologous TsF2 were mixed. Indirect evidence is presented that suggests that this restriction is because the chains fail to interact rather than the inability of the target cells to recognize both chains.

scholarly journals Presence of interchain disulfide bonds between two gene products that compose the secreted form of an antigen-specific suppressor factor.

1981 ◽  
Vol 153 (6) ◽  
pp. 1672-1677 ◽  
Author(s):  
M Taniguchi ◽  
T Saito ◽  
I Takei ◽  
T Tokuhisa
Keyword(s):  
T Cell ◽  
Disulfide Bonds ◽  
Active Form ◽  
Keyhole Limpet Hemocyanin ◽  
Antigen Binding ◽  
Gene Products ◽  
Suppressor Factor ◽  
T Cell Factor ◽  
Suppressor T Cell ◽  
Polypeptide Chains

The secreted form of the suppressor T cell factor specific for keyhole limpet hemocyanin derived from the hybridoma 34S-704 was found to consist of the two distinct polypeptide chains, i.e., the antigen-binding and the I-J-encoded chains. They were linked in covalent association with disulfide bonds. The two chains were cleaved by the reduction with dithiothreitol and were easy to reconstitute the active form of TsF. The association of the two distinct chains was suggested to be essential for the expression of the TsF activity.

scholarly journals Mechanisms of regulation of cell-mediated immunity. III. The characterization of azobenzenearsonate-specific suppressor T-cell-derived-suppressor factors.

1979 ◽  
Vol 149 (5) ◽  
pp. 1069-1083 ◽  
Author(s):  
M I Greene ◽  
B A Bach ◽  
B Benacerraf
Keyword(s):  
T Cell ◽  
Suppressor Cells ◽  
Binding Specificity ◽  
Delayed Type Hypersensitivity ◽  
Antigen Binding ◽  
Gene Products ◽  
Suppressive Activity ◽  
Spleen Cells ◽  
Suppressor Factor ◽  
Suppressor T Cell

Delayed type hypersensitivity to the hapten azobenzenearsonate (ABA) can be induced and suppressed by the administration of hapten-coupled syngeneic spleen cells by the appropriate route. Suppressor T cells stimulated by the intravenous administration of ABA-coupled spleen cells have been shown to produce a discrete subcellular factor(s) which is capable of suppressing delayed type hypersensitivity to azobenzenearsonate in the mouse. Such suppressor factors may be produced by the mechanical disruption of suppressor cells or by placing such suppressor cells in culture for 24 h. The suppressor factor(s) (SF) derived from ABA-specific suppressor cells exhibit biological specificity for the suppression of ABA delayed type hypersensitivity (DTH), but not trinitro-phenyl DTH, as well as the capacity to bind to ABA immunoadsorbents. Passage of suppressor factor(s) over reverse immunoadsorbents utilizing a rabbit anti-mouse F(ab')2 antiserum demonstrated that the antigen-specific T-cell derived SF does not bear conventional immunoglobulin markers. The suppressor factor(s) are not immunoglobulin molecules was further demonstrated by the inability of anti-ABA antibodies to suppress ABA DTH. Gel filtration of ABA suppressor factor(s) showed that the majority of the suppressive activity was present in a fraction with molecular weight ranging between 6.8 x 10(4) and 3.3 x 10(4) daltons. We also analyzed for the presence of determinants encoded by the H-2 major histocompatibility complex (MHC) and found that immunoadsorbents prepared utilizing antisera capable of interacting with gene products of the whole or selected gene regions of H-2 MHC, i.e., B10.D2 anti-B10.A and B10 anti-B10.A immunoadsorbents, retained the suppressive activity of ABA-SF. Elution of such columns with glycine HCl buffers (pH 2.8) permitted recovery of specific suppressive activity. Taken collectively such data supports the notion that suppressor T-cell-derived ABA suppressor factors have antigen-binding specificity as well as determinants controlled by the K end of the H-2 MHC. The distribution of strains capable of making SF has also been analyzed. The relationship of the antigen-binding specificity to VH gene products is discussed in this and the companion paper.

scholarly journals Identification of Igh-C-linked determinants on suppressor T cell hybrids and factors specific for L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT).

1985 ◽  
Vol 162 (3) ◽  
pp. 1044-1059 ◽  
Author(s):  
C M Sorensen ◽  
R J Hayashi ◽  
C W Pierce
Keyword(s):  
T Cells ◽  
T Cell ◽  
Polypeptide Chain ◽  
Spleen Cells ◽  
Suppressor T Cell ◽  
Cell Hybrids ◽  
Single Polypeptide Chain ◽  
Functional Classes ◽  
Single Polypeptide ◽  
Ig Allotype

Hyperimmunization of BALB/c mice with concanavalin A-stimulated blasts from the Ig allotype-congenic strain, C.B20, results in the production of antibodies reactive with T cells in an allotype-restricted manner. Spleen cells from these hyperimmune BALB/c mice were used to generate a panel of hybridomas that secrete monoclonal antibodies, reactive, in an allotype-restricted manner, exclusively with T cells subpopulations, and in particular, reactive with suppressor T cell hybridomas and their secreted soluble factors. Two functional classes of antibodies were identified: those that react with single polypeptide-chain suppressor T cell factors (TsF1) and the suppressor T cell hybridomas that produce such factors, and those that react with two polypeptide-chain suppressor T cell factors (TsF2) and their corresponding suppressor T cell hybridomas. These two classes of antibody were used to isolate molecules from the membranes of the respective suppressor T cell hybrids that are functionally and structurally related to the secreted suppressor T cell factors, suggesting a receptor function for these molecules.

scholarly journals Cell-type-specific cytotoxicity of anti-CD4 and anti-CD8 ricin immunotoxins against human alloreactive T-cell clones

Blood ◽  
1989 ◽  
Vol 74 (7) ◽  
pp. 2445-2454 ◽  
Author(s):  
FM Uckun ◽  
DE Myers ◽  
JA Ledbetter ◽  
SL Wee ◽  
DA Vallera
Keyword(s):  
T Cell ◽  
Cell Subset ◽  
Target Cells ◽  
Cell Type ◽  
T Cell Clones ◽  
First Order ◽  
Cell Clones ◽  
T Cell Clone ◽  
Cell Type Specific ◽  
Alloreactive T Cell

Abstract Potent T-cell subset-directed immunotoxins (ITs) were generated by conjugating the anti-CD4 monoclonal antibody (MoAb) G17–2 and the anti- CD8 MoAb G10.1 to the ribosome-inhibitory protein, ricin. The cell-type- specific cytotoxicities of the generated ITs were evaluated at the clonal level using human alloreactive T-cell clones. The kinetics of anti-CD4 ricin-induced inactivation of protein synthesis in target CD4+ cloned T-cells was first order with no detectable lag period and a maximum rate of 0.07 logs per hour (t10 = 13.6 hours; first-order rate constant/K = 0.17 hr-1). The alloantigen specific lytic function of the CD4+ cytolytic T-cell clone JMAC28 was acutely sensitive to anti-CD4 ricin, and no residual lytic activity against allogeneic targets was detectable 24 hours after treatment with as little as 0.5 mmol/L anti- CD4 ricin. Notably, both anti-CD4 ricin and anti-CD8 ricin elicited a selective and dose-dependent inhibition of clonal proliferation of target T-cell clones with a maximum kill of greater than 3 logs at 5 nmol/L. No significant “bystander effects” were observed for non-target cells. Bone marrow progenitor cells CFU-GM, BFU-E, and CFU-GEMM were only minimally affected by either IT. We conclude that these ITs show considerable potential for effective depletion of T-cell subpopulations from allogeneic donor marrow grafts for clinical graft-versus-host disease (GVHD) prophylaxis.

scholarly journals The nonpolymorphic MHC Qa-1b mediates CD8+ T cell surveillance of antigen-processing defects

2009 ◽  
Vol 207 (1) ◽  
pp. 207-221 ◽  
Author(s):  
Cláudia C. Oliveira ◽  
Peter A. van Veelen ◽  
Bianca Querido ◽  
Arnoud de Ru ◽  
Marjolein Sluijter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Antigen Processing ◽  
Germ Line ◽  
Wide Spectrum ◽  
Cell Subset ◽  
Target Cells ◽  
Peptide Epitopes ◽  
Leader Peptides

The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b–restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying with the conserved nature of Qa-1b. Target cell recognition depended on T cell receptor and Qa-1b interaction, and immunization with identified peptide epitopes demonstrated in vivo priming of CD8+ T cells. Our data reveal that Qa-1b, and most likely its human homologue human leukocyte antigen-E, is important for the defense against processing-deficient cells by displacing the monomorphic leader peptides, which relieves the inhibition through CD94/NKG2A on lymphocytes, and by presenting a novel repertoire of immunogenic peptides, which recruits a subset of cytotoxic CD8+ T cells.

Human Minor Histocompatibility Antigen-Specific CD8+ T Cells Are Found Predominantly in the CD45RA+ CD62L+ Naïve T Cell Subset.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 578-578 ◽  
Author(s):  
Marie Bleakley ◽  
Audrey Mollerup ◽  
Colette Chaney ◽  
Michele Brown ◽  
Stanley R. Riddell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
Target Cells ◽  
Screening Assay ◽  
Memory T Cell ◽  
Alloreactive T Cells ◽  
Selective Depletion

Abstract Graft versus host disease (GVHD) after allogeneic stem cell transplant (SCT) is initiated by the activation of alloreactive T cells by host dendritic cells (DC) in lymphoid tissue. Studies in murine models have demonstrated that selective depletion of naïve T cells abrogates GVHD in major and minor histocompatibility antigen (miH) mismatched SCT and provides for rapid reconstitution of memory T cell responses to pathogens. This suggests the memory subset may lack a sufficient repertoire of alloreactive T cells or fail to localize to sites where GVHD is initiated. If such a strategy were effective in humans, morbidity from GVHD would be reduced, but the graft versus leukemia (GVL) effect might be compromised. To explore the potential of this approach in humans, we developed a novel limiting dilution assay using DC as stimulator cells in vitro to analyze the frequency and repertoire of human miH reactive T cells in highly purified naïve and memory T cell subsets obtained from HLA identical volunteer donor pairs. For each pair, mature DC were derived by differentiation of CD14+ monocytes in vitro from one volunteer, and pure (>97%) populations of naïve (CD62L+, CD45 RA+, CD45RO-) and memory (CD45RO+) CD8 T cells were obtained by FACS sorting of CD8 enriched PBMC from the respective HLA identical sibling. Memory and naïve T cells were cultured for 12 days in 96 well plates at a range of concentrations with DC at a 30:1 ratio and IL12 (10 ng/ml), and IL15 (10 ng/ml) was added on day 7. On day 12, the wells were screened against target cells from each volunteer in a chromium release assay (CRA) to quantitative T cells with reactivity against miH. All wells with reactivity in this screening assay were subsequently expanded using anti CD3 antibody and IL2 and retested by CRA to validate the results of the screening assay. In multiple experiments using different HLA matched pairs, T cells with specific and reproducible cytotoxic activity (>15% lysis) against target cells from the DC donor but not autologous targets were only isolated from wells plated with naïve CD8 T cells, and there was no reproducible cytotoxicity from wells plated with memory T cells. This data demonstrates that miH specific CD8 T cells are found predominantly, and possibly exclusively, in the naïve T cell subset in humans. This data is consistent with a dramatically reduced repertoire of miH alloreactive T cells in the memory T cell pool and supports the development of protocols to prevent GVHD by selective depletion of CD45RA+ CD8+ T cells from the hematopoietic cell graft. However, T cells specific for miH also contribute to the GVL effect and CD45RA depletion would be expected to compromise antileukemic activity. Using the above approach for isolating miH specific CTL from naïve CD8 T cells, we have found a diverse repertoire of alloreactivity in most cultures and identified a subset of T cell lines and clones specific for miH presented selectively on hematopoietic cells. These T cells recognize primary ALL and AML samples that express the restricting HLA allele in vitro. MiH specific T cell clones can be reliably generated by this method using DC derived from monocytes of patients with advanced leukemia. Thus, it may be feasible to utilize this approach to isolate T cells specific for hematopoietic restricted miH for adoptive therapy as an adjunct to CD45RA depletion to preserve the GVL effect and allow separation of GVL from GVHD.

scholarly journals Acceptor-suppressor T cell hybridoma with a receptor recognizing antigen-specific suppressor factor.

1983 ◽  
Vol 158 (6) ◽  
pp. 1912-1923 ◽  
Author(s):  
I Takei ◽  
T Sumida ◽  
M Taniguchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antibody Response ◽  
Keyhole Limpet Hemocyanin ◽  
Acceptor Site ◽  
Suppressor Factor ◽  
T Cell Factor ◽  
Suppressor T Cell ◽  
Antigen System ◽  
Petri Dishes

An acceptor hybridoma with a receptor that recognizes the keyhole limpet hemocyanin (KLH)-specific suppressor T cell factor (KLH-TsF) was established after the fusion of C57BL/6 splenic T cells enriched with KLH-coated petri dishes. The cloned hybridoma (34S-281) could be specifically activated by stimulation with the conventional KLH-TsF or monoclonal KLH-TsF from three different hybridomas in the absence of the relevant antigen (KLH) and it started to produce another factor that suppresses the antibody response against DNP-KLH in a KLH-specific fashion. The KLH specificity of the TsF was required for activation. The new factor was found not to bind the KLH but to be absorbed with the KLH-TsF-producing hybridoma. It is thus strongly suggested that the acceptor site has a complementary structure (antiidiotype) for the KLH-TsF. Moreover, the idiotypic determinant on KLH-TsF was found to have a structure similar to that on some of the anti-KLH antibodies, since the acceptor hybridoma was specifically killed by the conventional anti-KLH antibodies and complement. Drawing on the above results, the idiotype-antiidiotype network in the conventional antigen system is discussed.

scholarly journals Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2269-2279 ◽  
Author(s):  
Christelle Harly ◽  
Yves Guillaume ◽  
Steven Nedellec ◽  
Cassie-Marie Peigné ◽  
Hannu Mönkkönen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Subset ◽  
Cell Receptor ◽  
Causal Link ◽  
Target Cells ◽  
Γδ T Cell ◽  
Vγ9vδ2 T Cells

Abstract Human peripheral Vγ9Vδ2 T cells are activated by phosphorylated metabolites (phosphoagonists [PAg]) of the mammalian mevalonate or the microbial desoxyxylulose-phosphate pathways accumulated by infected or metabolically distressed cells. The underlying mechanisms are unknown. We show that treatment of nonsusceptible target cells with antibody 20.1 against CD277, a member of the extended B7 superfamily related to butyrophilin, mimics PAg-induced Vγ9Vδ2 T-cell activation and that the Vγ9Vδ2 T-cell receptor is implicated in this effect. Vγ9Vδ2 T-cell activation can be abrogated by exposing susceptible cells (tumor and mycobacteria-infected cells, or aminobisphosphonate-treated cells with up-regulated PAg levels) to antibody 103.2 against CD277. CD277 knockdown and domain-shuffling approaches confirm the key implication of the CD277 isoform BTN3A1 in PAg sensing by Vγ9Vδ2 T cells. Fluorescence recovery after photobleaching (FRAP) experiments support a causal link between intracellular PAg accumulation, decreased BTN3A1 membrane mobility, and ensuing Vγ9Vδ2 T-cell activation. This study demonstrates a novel role played by B7-like molecules in human γδ T-cell antigenic activation and paves the way for new strategies to improve the efficiency of immunotherapies using Vγ9Vδ2 T cells.

Suppressor T-Cell Hybridoma with a Receptor Recognizing KLH-Specific Suppressor Factor

1984 ◽  
pp. 435-447
Author(s):  
Masaru Taniguchi ◽  
Izumi Takei ◽  
Takayuki Sumida ◽  
Masamoto Kanno ◽  
Masatoshi Tagawa ◽  
...  
Keyword(s):  
T Cell ◽  
Suppressor Factor ◽  
Suppressor T Cell

scholarly journals Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates.

1993 ◽  
Vol 177 (4) ◽  
pp. 979-987 ◽  
Author(s):  
A Geluk ◽  
D G Elferink ◽  
B L Slierendregt ◽  
K E van Meijgaarden ◽  
R R de Vries ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Amino Acid ◽  
T Cell ◽  
Binding Site ◽  
Rhesus Macaque ◽  
Peptide Binding ◽  
Antigen Binding ◽  
Amino Acid Residues ◽  
Antigen Binding Site ◽  
Histocompatibility Complex

Many major histocompatibility complex (MHC) polymorphisms originate from ancient structures that predate speciation. As a consequence, members of the Mhc-DRB1*03 allelic lineage are not only present in humans but in chimpanzees and rhesus macaques as well. This emphasizes that Mhc-DRB1*03 members must have been present in a common ancestor of these primate species that lived about 30 million years ago. Due to the accumulation of genetic variation, however, alleles of the Mhc-DRB1*03 lineage exhibit species-unique sequences. To investigate the biological importance of such conservation and variation, we have studied both the binding and antigen presentation capacity of various trans-species Mhc-DRB1*03 lineage members. Here we show that p3-13 of the 65-kD heat-shock protein (hsp65) of Mycobacterium leprae and M. tuberculosis binds not only to HLA-DR17(3) but also to some chimpanzee and rhesus macaque class II-positive cells. Comparison of the corresponding human, chimpanzee, and rhesus macaque Mhc-DRB1*03 lineage members revealed the presence of uniquely shared amino acid residues, at positions 9-13 and 26-31, of the antigen-binding site that are critical for p3-13 binding. In addition it is shown that several nonhuman primate antigen-presenting cells that bind p3-13 can activate HLA-DR17-restricted T cells. Certain amino acid replacements, however, in Mhc-DRB1*03 lineage members did not influence peptide binding or T cell recognition. Therefore, these studies demonstrate that some polymorphic amino acid residues (motifs) within the antigen-binding site of MHC class II molecules that are crucial for peptide binding and recognition by the T cell receptor have been conserved for over 30 million years.

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