Peptides corresponding to T-cell receptor-HLA contact regions inhibit class I-restricted immune responses.
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Amino Acid Sequence↗
Biomedical subjects
A M Krensky
Publications and source records attributed to A M Krensky.
Peptides corresponding to the CD8 binding region of HLA class I block the differentiation of cytotoxic T lymphocyte precursors.
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Animals↗
Human cytotoxic T-lymphocytes specific for autologous follicular lymphoma recognize immunoglobulin in a major histocompatibility complex restricted fashion.
BACKGROUND: Previously, autologous Burkitt lymphoma-specific cytotoxic T-lymphocytes (CTL) were found to express the gamma and delta T-cell receptor and recognize tumor idiotype in a major histocompatibility complex (MHC) unrestricted fashion. METHODS: In this study, the authors established autologous CTL lines and clones specific for a B-cell follicular lymphoma. RESULTS: These CTL are tumor specific and inhibited by antiimmunoglobulin monoclonal antibodies, but unlike the Burkitt lymphoma-specific CTL, they are MHC restricted and express the alpha and beta T-cell receptor. CONCLUSIONS: These studies suggest that different B-cell lymphomas can induce CTL of different phenotypes and MHC restriction.
Adult↗
Genomic structure and alternative splicing of 519, a gene expressed late after T cell activation.
Relatively little is known about the transcriptional control of genes expressed late after T cell activation. We have identified four genes expressed 3 to 5 days after T cell activation by alloantigen or mitogen. Here we report the genomic organization of 519, one of these late T cell activation Ag. Analysis of the genomic clone revealed that 519 consists of six exons. Ribonuclease protection experiments indicated that the most abundant transcript arising from this region is an alternatively spliced form of 519, referred to as 520, which lacks exon 2 and is similar in sequence to NKG5, a cDNA identified in NK cells. These experiments also revealed the existence of two other alternatively spliced RNA transcripts, with heterogeneity in exon 2. Primer extension analysis and ribonuclease protection assays demonstrated that there are two prominent start sites for transcription; however, there is no evidence for the NKG5 transcript in T cells, indicating that NKG5 may represent a NK cell-specific form of 520. The 5' flanking region of this gene contains several previously identified sequences involved in transcriptional regulation, as well as some potentially interesting novel conserved motifs.
Antigens, Differentiation, T-Lymphocyte↗
Identification and molecular cloning of tactile. A novel human T cell activation antigen that is a member of the Ig gene superfamily.
We have identified and cloned cDNA for a novel cell-surface protein that we have named Tactile for T cell activation, increased late expression. It is expressed on normal T cell lines and clones, and some transformed T cells, but no other cultured cell lines tested. It is expressed at low levels on peripheral T cells and is strongly up-regulated after activation, peaking 6 to 9 days after the activating stimulus. It is also up-regulated on NK cells activated in allogeneic cultures. It is not found on peripheral B cells but is expressed at very low levels on activated B cells. Tactile-specific mAb immunoprecipitates a band of 160 kDa when reduced and bands of 240, 180, and 160 kDa nonreduced. Using an antiserum produced with affinity-purified Tactile protein to screen a lambda gt11 library, we have identified Tactile cDNA. Northern blot analysis shows an expression pattern similar to that of the protein and transfection of COS cells with the full-length 5.2-kb cDNA results in cell-surface expression. Comparison with the sequence databanks show that Tactile is a member of the immunoglobulin gene superfamily, with similarity to Drosophila amalgam, the melanoma Ag MUC-18, members of the carcinoembryonic Ag family, the poliovirus receptor, and the neural cell adhesion molecule. The deduced primary sequence encodes a protein with three Ig domains, a long serine/threonine/proline-rich region typical of an extensively O-glycosylated domain, a transmembrane domain, and a 45 residue cytoplasmic domain. These data suggest that Tactile may be involved in adhesive interactions of activated T and NK cells during the late phase of the immune response.
Amino Acid Sequence↗
Anchoring pockets in human histocompatibility complex leukocyte antigen (HLA) class I molecules: analysis of the conserved B ("45") pocket of HLA-B27.
Dissection of the peptide binding grooves of seven subtypes of human histocompatibility leukocyte antigen (HLA)-B27 into the six specificity pockets defined by the 2.6-A structure of HLA-A*0201 revealed just one pocket, the B ("45") pocket, that is conserved among all the HLA-B27 subtypes. Functional studies of mutant HLA-B*2705 molecules with point substitutions in residues of the B pocket show that this structure, and the glutamine residue at position 45 in particular, plays a critical role in cell surface expression, peptide binding, and in the presentation of both exogenous and endogenous peptides by HLA-B*2705. We predict that the B pocket of HLA-B*2705 interacts with an amino acid side chain that anchors peptides in the binding groove, and that this peptide motif is present in most endogenously processed peptides that bind to all seven subtypes of HLA-B27.
Amino Acid Sequence↗
Interleukin 3 is a growth factor for human follicular B cell lymphoma.
More than one-half of adults with non-Hodgkin's B cell lymphomas present with low-grade follicular lymphomas. These tumor cells are found in close association with follicular T lymphocytes and dendritic cells, suggesting that the surrounding cells may play a role in the support of follicular tumors. Supernatants from activated human peripheral blood lymphocytes were found to promote the in vitro proliferation of follicular tumor cells. This effect was entirely due to interleukin 3 (IL-3), a factor generally thought to cause the growth and differentiation of immature hematopoietic cells. IL-3 receptors were detected on fresh isolates of all primary follicular cell tumors examined. These findings suggest that follicular cell tumors may be dependent in vivo on IL-3 and that therapies directed against IL-3, its receptor, or the T cells that produce it may be effective treatment for follicular lymphoma.
Cell Division↗
Isolation and characterization of cDNA from renal tubular epithelium encoding murine Rantes.
We have been interested in identifying proinflammatory molecules which might play a role in attracting monocytes and T cells to the kidney. Some of the new intercrines are potential candidates. In this report we have isolated cDNA encoding murine Rantes (MuRantes) from renal tubular epithelium (MCT cells). MuRantes is a 91 amino acid member of the -C-C- or intercrine beta subgroup of the Scy superfamily. The amino acid sequence for mature MuRantes was deduced from its coding cDNA and was found to be 90% homologous to its mature human counterpart (HuRantes). MCT epithelium expresses a single mRNA transcript for MuRantes of approximately 1100 bp. The MuRantes protein could be detected in cell lysates of MCT epithelium by western blotting and in the cytoplasm of MCT cells by immunofluorescence using a polyclonal antibody generated against HuRantes fusion protein. A search protocol using MuRantes-specific primers and cDNA amplification revealed that mRNAs for MuRantes are expressed additionally in syngeneic mesangial cells (MMC cells), whole kidney, liver, and spleen, as well as in nephritogenic antigen-specific CD4+ helper and CD8+ effector T cells. cDNA amplification studies also demonstrated a significant elevation in mRNA transcripts encoding MuRantes in response to the stimulation of MCT epithelium with TNF alpha and IL-1 alpha in culture, but not with TGF beta, gamma IFN, or IL-6. Our findings indicate that proximal tubular epithelium is an authentic source of MuRantes, and that transcripts encoding MuRantes are responsive to the modulating influence of paracrine factors having a known role in the development of parenchymal injury.
Amino Acid Sequence↗
Generation of monoclonal antibodies against soluble human T cell receptor polypeptides.
One approach to the diagnosis and therapy of T cell-mediated diseases is to develop reagents specific for T cell receptor (TcR) variable (V) regions. To date, however, TcR expressed on the surface of antigen-specific T lymphocytes have proven to be poorly immunogenic. As a result, few monoclonal antibodies (mAb) recognizing human variable regions are available. In this report, we have used the "phosphatidylinositol linkage" strategy to generate soluble forms of two human allogeneic TcR derived from human cytotoxic T lymphocytes (CTL) known to be specific for HLA-A2 and HLA-Aw68/HLA-Aw69, respectively. Monomeric TcR alpha and beta chains from the HLA-A2-specific CTL were purified in large quantities from CHO cells and each was used to immunize mice to generate mAb. In particular, the anti-beta chain mAb, denoted anti-V beta 13, stain a significant (approximately 5%) fraction of human peripheral blood alpha/beta T lymphocytes, immunoprecipitate native anti-A2 TcR molecules, and activate T cells transfected with the relevant alpha and beta chain cDNA. Anti-alpha chain mAb were also obtained against a constant region determinant which can immunoprecipitate detergent-solubilized polypeptides. In general, we find that immunizations with soluble protein are far superior to those with cells bearing TcR chimeras or in combination with the purified protein.
Amino Acid Sequence↗
Molecular basis of transplant rejection and acceptance.
The field of kidney transplantation is advancing so rapidly that it is difficult to keep up with the various therapeutic protocols, let alone our current understanding of transplantation immunobiology. This basic science review summarizes our current understanding of aspects of the cellular and molecular basis of renal transplant rejection and then details studies from the author's laboratory designed to specifically interrupt transplant rejection. The interaction of HLA with T cell receptors and the cascade of events following T cell activation are highlighted.
Graft Rejection↗
Lymphocyte adhesion molecules in T cell-mediated lysis of human kidney cells.
The complementary adhesion molecules LFA-1 (CD11a, 18)/ICAM-1 (CD54) and LFA-2 (CD2)/LFA-3 (CD58) have been shown to be important in T cell interaction with lymphoid target cells. The role of these ligand pairs in cytotoxicity against somatic cells is less well established. While LFA-3 is expressed by all cells in the kidney, ICAM-1 expression is low in normal kidneys but is increased in allograft rejection. An in vitro cytotoxicity assay was used to examine the relative importance of the two adhesion ligands in immune damage against kidney cells in rejection. HLA-A2 specific cytotoxic T lymphocyte (CTL) recognition of cultured human kidney cells (HKC), of predominantly renal tubular cell origin, was studied. Immunofluorescence studies showed that both induced and uninduced HKC target cells expressed ICAM-1, MHC class I and LFA-3, but only MHC class I and class II antigens and ICAM-1 were significantly upregulated by cytokine induction. Effector cells expressed LFA-1 and LFA-2 but little or no ICAM-1 and LFA-3. Cytokine induction of ICAM-1 expression on HKC target cells increased their susceptibility to lysis. Monoclonal antibody against ICAM-1 or LFA-1 produced the greatest inhibition of HKC lysis, and their effects were not additive. Antibody against LFA-2 (CD2) or LFA-3 also produced significant inhibition, but to a lesser degree, and no additive effect was found.(ABSTRACT TRUNCATED AT 250 WORDS)
Antibodies, Monoclonal↗
Recognition of an HLA public determinant (Bw4) by human allogeneic cytotoxic T lymphocytes.
The human class I HLA molecules are composed of both polymorphic, or private, and conserved, or public, regions. The private regions are recognized by alloreactive T cells and also serve as restriction elements for peptide presentation to autologous cells. Although the ability of public determinants to elicit antibody responses is well documented, little is known of their role in T cell function. In this study we examine the ability of one of these public HLA determinants, designated Bw4, to serve as a target Ag for CTL. We show that for some individuals the HLA-Bw4 epitope can function as a restriction element for CTL. This finding has important implications for organ transplantation.
Amino Acid Sequence↗
A binding site for the T-cell co-receptor CD8 on the alpha 3 domain of HLA-A2.
Adhesion measurements between CD8 and 48 point mutants of HLA-A2.1 show that the CD8 alpha-chain binds to the alpha 3 domain of HLA-A2.1. Three clusters of alpha 3 residues contribute to the binding, with an exposed, negatively charged loop (residues 223-229) playing a dominant role. CD8 binding correlates with cytotoxic T-cell recognition and sensitivity to inhibition by anti-CD8 antibodies. Impaired alloreactive T-cell recognition of an HLA-A2.1 mutant with reduced affinity for CD8 is not restored by functional CD8 binding sites on an antigenically irrelevant class I molecule. Therefore, complexes of CD8 and the T-cell receptor bound to the same class I major histocompatibility complex molecule seem to be necessary for T-cell activation.
Antigens, CD↗
T-lymphocyte-antigen interactions in transplant rejection.
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Animals↗
Molecular cloning and characterization of WP34, a phosphorylated human lymphocyte differentiation and activation antigen.
An absorbed antiserum was made by incubating a cytotoxic T lymphocyte immune antiserum with the T cell leukemia HPB-ALL, thus removing reactivity to known lymphocyte function-associated antigens. This antiserum was used to screen a cDNA expression library and isolate a novel human lymphocyte cDNA clone designated WP34, WP34 transcript is expressed in functional T cells and a variety of hematopoietic cell lines and tissues, including fetal liver and thymus, but not in HPB-ALL or any non-hematopoietic cell lines or tissues tested. The WP34 protein is an acidic, phosphorylated molecule with a pI of 4.5 and molecular mass of 50 kDa. WP34 protein expression is absent in resting peripheral blood lymphocytes but can be induced with antigen stimulation, while the transcript is constitutively expressed. Sequence analysis indicates that WP34 is the human homologue of the recently described murine molecule LSP1.
Amino Acid Sequence↗
Continuous venovenous hemofiltration.
Continuous venovenous hemofiltration (CVVH) is a technique characterized by a venovenous circuit and a pump to perfuse the hemofilter. CVVH is suited to individualization of ultrafiltration and solute clearance in patients with acute renal failure and volume overload, specifically when there is impaired cardiovascular function or where arterial access is problematic. Examples, indications and relative advantages of this and other dialytic modalities are discussed.
Acute Kidney Injury↗
Treatment of steroid-resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents.
In children, steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) is frequently a progressive condition resulting in end-stage renal disease. There have been no reports of effective treatment for this condition. For the past several years, the Pediatric Nephrology services at the University of California, San Diego and Stanford University Schools of Medicine have treated these patients with a protocol involving infusions of high doses of methylprednisolone, often in combination with oral alkylating agents. Twenty-three children have been treated in this manner with a follow-up of 46 +/- 5 months. Twelve of these children are in complete remission. Six have minimal to moderate proteinuria. Four children remain nephrotic. Each of these children has a normal glomerular filtration rate. One child developed chronic renal failure and subsequently died while on dialysis. These results appear significantly better than previous series of children with FSGS. A controlled, multi-center trial of this protocol has been proposed.
Adolescent↗
Localization of a human T-cell-specific gene, RANTES (D17S136E), to chromosome 17q11.2-q12.
We report here the localization of the gene for a human T-cell-specific molecule, designated RANTES, to human chromosome region 17q11.2-q12 by in situ hybridization and analysis of somatic cell hybrids using a cDNA probe to the gene. We have recently shown that this gene, which encodes a small, secreted, putative lymphokine, is a member of a larger gene family some of whose members reside on chromosome 4 but most of whose members have not to date been mapped. A secondary hybridization peak was noted on the region of human chromosome 5q31-q34, which may represent the location of other members of the gene family. Interestingly, this latter region overlaps with the location of an extended linked cluster of growth factor and receptor genes, some of which may be coregulated with members of the RANTES gene family.
Amino Acid Sequence↗