Search PubMed⌕ Search

Biomedical subjects

C Clayberger

Publications and source records attributed to C Clayberger.

At least 109 records · Page 6Linked to original sources
PubMed1985

Activation requirements of cloned inducer T cells. I. Differential inhibition by anti-L3T4 or anti-I-A is determined by the accessory cell population.

We have described a trinitrophenyl (TNP)-specific inducer clone, clone Ly-1-T1, which responds to a variety of different stimuli, including a) soluble TNP-protein conjugates plus syngeneic (H-2d) spleen cells, b) TNP directly coupled to syngeneic or allogeneic spleen cells, and c) activated I-A identical B cells in the absence of nominal antigen. In the present study we used a panel of antibodies to investigate the recognition structures involved in the activation of clone Ly-1-T1 by these different stimuli. We show that allogeneic spleen cells must be conjugated by using relatively high concentrations of TNBS to be efficient stimulators of the clone. In contrast, syngeneic spleen cells conjugated by using a much wider range of concentrations will activate the clone. The response of the clone to TNP-coupled allogeneic spleen cells is inhibited by anti-L3T4 and anti-Ia antibodies. In contrast, stimulation of the clone with syngeneic spleen cells coupled by using the same concentrations of TNBS is not inhibited with either anti-Ia or anti-L3T4 antibody. The inhibition pattern observed with anti-Ia and anti-L3T4 antibodies was also determined by the nature of the accessory population used to present soluble TNP-protein conjugates. Anti-I-Ad antibodies blocked the activation of clone Ly-1-T1 by TNP-protein plus splenic adherent cells, indicating the involvement of polymorphic I-A determinants in this response. Anti-L3T4 antibody had little or no effect on this response, suggesting that a significant L3T4-Ia interaction is not required. Finally, the response of the clone to activated B cells in the presence or absence of TNP-protein is exquisitely sensitive to inhibition by anti-L3T4 as well as anti-I-A antibodies. The data suggest that the requirement for an L3T4-I interaction depends on the combination of antigen and accessory cell type used to stimulate the clone.

Animals↗
PubMed1985

Heritable lymphocyte function-associated antigen-1 deficiency: abnormalities of cytotoxicity and proliferation associated with abnormal expression of LFA-1.

The effect of heritable LFA-1 deficiency on T lymphocyte function was measured. After primary mixed lymphocyte stimulation, all six patients studied showed diminished allospecific T lymphocyte cytolytic and NK activity as compared with kindred and normal controls. MLR and mitogen-induced proliferative responses were consistently depressed. LFA-1-deficient, EBV-transformed B cell lines were poor stimulators of T cell responses. Primary cytolytic responses by lymphocytes from severely LFA-1-deficient patients (less than 0.2% of normal surface expression) were consistently more profoundly depressed than those by lymphocytes from moderately deficient patients (about 5% of normal surface expression). These results demonstrate the importance of LFA-1 in lymphocyte function. After repeated MLR restimulation, proliferative and cytolytic capacity improved and CTL lines could be established from all patients. Cytolysis by lines from one but not a second severe patient, and by four of four moderate patients, was inhibited by anti-LFA-1 MAb, and at 10-fold lower concentrations than required for inhibition of killing by control CTL lines. The locus of inhibition was on the target cell for the severely deficient CTL line, and on both the target and effector cells for moderately deficient CTL lines. In contrast, the locus of inhibition for normal CTL is on the effector cell. These findings show that LFA-1 can participate bidirectionally in cell interactions. The in vitro results are discussed in terms of the clinical findings in patients.

Antibodies, Monoclonal↗
PubMed1985

Evidence for defects in accessory and T cell subsets in mice expressing the xid defect.

Mice expressing the X-linked recessive CBA/N genetic defect xid lack a subpopulation of B cells which appears late in normal B cell ontogeny and is characterized by expression of the cell surface antigens Lyb3, Lyb5, and Lyb7. In adult mice with the xid defect, responses to Type 2 antigens such as TNP-ficoll are entirely absent and responses to Type 1 antigens such as TNP-LPS are somewhat reduced. Primary in vitro responses to the T dependent antigen sheep red blood cells (SRBC) are defective but secondary responses are normal. These and other findings have led to the hypothesis that one effect of the xid defect is the inability of a subset of B cells to respond to nonspecific signals from T cells or accessory cells. The cellular basis of the xid defect is not well understood. The simplest explanation is that it reflects a primary lesion in the development of a subpopulation of B cells responsible for the types of immune responses described above. An alternative notion is that the xid defect is expressed primarily in a non-B cell population (e.g., T cells or accessory cells) which are necessary for the development and/or function of this B cell subset. A direct approach to this problem depends on the availability of homogeneous populations of B cells, T cells, or accessory cells. Recently we have described a cloned dendritic cell, Den-1, which is a potent stimulator of some B and T cell responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Interactions of T lymphocytes with human vascular endothelial cells: role of endothelial cells surface antigens.

We have studied the interactions of peripheral blood T lymphocytes with cultured human vascular endothelial cells, focusing upon endothelial cell surface antigens important for T cell recognition. Under standard culture conditions endothelial cells express class I but not class II major histocompatibility complex (MHC) antigens. However, class II antigens may be induced by activated T cells or T cell products, including the lymphokine immune interferon. Immune interferon concomitantly increases class I antigen expression and causes a change in cell shape. In addition to vascular endothelial cells, we have found that vascular smooth muscle cells and human dermal fibroblasts may also be induced by immune interferon to express class II antigens. All known human class II antigens are induced (i.e. HLA-DR, DC and SB) as is the associated invariant chain. Induced antigen expression in these cells is stable over several days, although mRNA levels decline rapidly upon withdrawal of interferon. Vascular and stromal cell class II antigens are functional, in that they can be recognized by cytolytic and helper T cell clones. Several non-MHC antigens are also involved in the recognition of endothelial and stromal cells by T cells. We propose a model for the role of inducible class II molecules on endothelium and stromal cells in vivo: The induction of class II MHC antigens on endothelial cells, locally mediated by activated T cells, enables endothelium to present an immunogenic cell surface structure, comprised of antigen plus self class II polymorphic determinants, which in turn, serves to recruit additional antigen-specific T cells from the circulation into the site of a developing cell mediated immune response. Class II molecules on stromal cells, also induced locally at the site of a developing response, confers immune accessory function on these cells and may serve to augment and sustain a T cell response.

Antigen-Presenting Cells↗
PubMed1984

Immunoregulatory activities of autoreactive T cells: an I-A-specific T cell clone mediates both help and suppression of antibody responses.

We have derived a Ly-1+, 2-3- T cell clone that is specific for autologous I-A on activated but not on resting cells. After activation, this clone produces factors that induce purified (B + adherent) cells to secrete antibody in response to sheep red blood cells and type 2 T-independent antigens. Regulation of plaque-forming cell responses by this clone is dose dependent: low numbers enhance the plaque-forming cell response, whereas high numbers suppress the response. The inhibition observed with high doses is associated with cytolysis of I-A+ cells, and this can be blocked by the addition of anti-I-A antibodies. The physiologic significance of this novel cell type in regulating immune responses is discussed.

Animals↗
PubMed1984

Immunoregulation of T-dependent responses by a cloned dendritic cell.

We have described a cloned dendritic cell, Clone Den-1, which is a potent accessory cell for some T-dependent immune responses. Clone Den-1 activates T cells in both autologous and allogeneic mixed lymphocyte reactions, but cannot present soluble antigen to T cells that co-recognize nominal antigen plus I-Ab gene products. In addition, Clone Den-1 or factors produced by it can reconstitute plaque-forming cell responses by accessory cell-depleted B plus T cells to the T-dependent antigen sheep red blood cells. The relationship of this clone to heterogeneous populations of dendritic cells and other accessory cells is discussed.

Animals↗
PubMed1984

Human cytolytic T lymphocyte interactions with vascular endothelium and fibroblasts: role of effector and target cell molecules.

Monoclonal antibodies (mAb) against cell surface structures have been used to identify several molecules involved in the interaction of human cytolytic T lymphocytes (CTL) with lymphoid and other bone marrow-derived targets. In allograft rejection or in graft-vs-host disease, however, major cellular targets are vascular and stromal cells, especially endothelium. Yet little is known about whether the same cell surface molecules are involved in the interactions of CTL with these cell types. We assessed the ability of mAb against effector or target cell structures to inhibit cytolysis of susceptible, cultured human vascular endothelium or dermal fibroblasts by a cloned human CTL line. Using mAb reactive with T3, T4, LFA-1, LFA-2, LFA-3, and HLA-DR, we found a qualitatively similar but quantitatively different pattern of inhibition of cytolysis as previously established for lymphoid targets by using the same CTL clone. These results have two implications: 1) the target cell structures recognized by CTL molecules such as T4, LFA-1 and LFA-2 are present on diverse cell types; and 2) the relative importance of such interactions may vary with target cell type. Furthermore, our studies provide several insights into the mechanisms of the interacting molecules. Our model system, and the use of pathophysiologically important target cells, may be useful for further analysis of CTL-mediated immune injury.

Antibodies, Monoclonal↗
PubMed1983

Hapten reactive inducer T cells. II. Evidence that a secreted form of the T cell receptor induces antibody production.

The biologic activity of molecules synthesized and secreted by hapten-specific inducer T cells was examined. After activation, a single inducer clone secretes both antigen-specific inducer peptides as well as nonspecific factors. The nonspecific factors augment the in vitro response of B cells to sheep erythrocytes (SRBC) and Type 2 T-independent antigens. The antigen-specific molecules (ABM) induce plaque-forming cell (PFC) responses in cultures containing ABM, B cells, and antigen that links the epitope recognized by ABM with the B cell epitope. Induction of B cells by ABM is limited to B cells expressing the same I-A allele as the source of the ABM and this reflects binding by ABM to I-A products on B lymphocytes. The data reported here strongly support the view that inducer cells can activate at least some B cells by secretion of a modified form of the T cell surface receptor.

Animals↗
PubMed1983

Hapten-reactive inducer T cells. I. Definition of two classes of hapten-specific inducer cells.

Hapten-reactive inducer T cell clones can be divided into two groups based on their activation specificity. The first and largest group is conjugate specific. These clones are activated only by hapten coupled to the same carrier protein used for in vitro selection. The second group, which is quite rare, is hapten specific. Clones of this type are activated by hapten coupled to all foreign and autologus proteins tested. Both types of clones corecognize soluble antigen in association with products of the I-A locus. The hapten-specific cells were used to analyze the molecular basis of I-A vs. I-E gene control. The physiologic significance of hapten- and carrier-specific inducer T cells in the response to foreign antigens and autoantigens is discussed.

Animals↗
PubMed1983

Sequential expression of new gene programs in inducer T-cell clones.

We have prepared a cDNA probe that detects genes that are rapidly and abundantly expressed after exposure of inducer T-lymphocyte clones to antigen or mitogen. All inducer cells tested express a characteristic set of new mRNA, and these mRNAs are not expressed after activation of other lymphocytes. This initial burst of mRNA synthesis is paralleled by synthesis and secretion of a family of polypeptides that mediate inducer cell activity, including T- and B-cell growth factors, interferon, and molecules that bind to antigen. Expression of this initial genetic program precedes mitosis and is replaced within 74 hr by a different genetic program, which may control further cell division. The action of these sequential sets of genetic programs defines two stages of the cell's differentiation and accounts for altered expression of the cell's immunological functions.

Animals↗
PubMed1983

Cytotoxic T cells directed against HLA-DR antigens and their surface proteins.

The authors review their recent research involving the generation of cytotoxic T lymphocytes (CTL) directed against HLA-DR antigens. A mouse anti-human xenogeneic system first suggested that HLA-DR antigens could be recognized by CTL. Human allogeneic CTL specific for HLA-DR6 were generated and found to be OKT4+. The fact that these CTL were OKT4+ while anti HLA-A,B CTL were OKT8+ suggested that these T cell surface antigens may be involved in MHC antigen recognition; ie, they may be part of the T cell receptor. These OKT4+, HLA-DR specific CTL were further used to generate monoclonal antibodies (1) which block cytolysis and define novel antigens involved in the CTL-target interaction and (2) which define an antigenic complex on alloantigen activated T cells.

Animals↗
PubMed1983

A DC-specific cytolytic T lymphocyte line is OKT8+1.

A human cytotoxic T lymphocyte (CTL) line, A9, was generated by limiting dilution and was selected because of its apparent DC specificity. A9 is 100% OKT3+, 90% OKT4+, and 10% OKT8+, but by negative selection the CTL present are entirely OKT8+. These OKT8+ CTL are totally inhibitable by Genox 3.53, an anti-DC1 monoclonal antibody (mAb), and Leu-10, an anti-DC subgroup mAb, but are not inhibitable by a panel of anti-HLA-DR mAb. These CTL are also inhibitable by anti-OKT3 and anti-LFA-2 but not by OKT4 or OKT8 mAb. These findings extend previous studies that showed that OKT8+ CTL recognize HLA-A,B antigens, whereas OKT4+ CTL recognize HLA-DR and SB antigens. It is possible that an as yet undefined T cell surface molecule is involved in DC recognition.

Antibodies, Monoclonal↗
PubMed1982

Specificity of OKT4+ cytotoxic T lymphocyte clones.

OKT4+, HLA-DR-specific CTL were cloned by limiting dilution, and two clones were evaluated. One clone, B8, specifically recognized DR6 antigens, whereas another cloned, C6, recognized an Ia-like determinant on some DR 3, 5, and 6 target cells. Both clones were OKT3+, OKT4+, and OKT8-, and their cytolysis could be blocked by OKT3 and OKT4, but not OKT8, antibodies. A panel of monoclonal antibodies that recognize DR molecules blocked target cell recognition by these OKT+ CTL. Although cloned B8 recognized a DR6-specific determinant, clone C6 appeared to recognize a supratypic determinant that may be common to some DR molecules (e.g., MT2) or possibly another human Ia-like antigen (e.g., SB). The availability of OKT+ CTL clones should help to dissect the Ia-like antigens recognized by human T cells.

Antibodies, Monoclonal↗
PubMedDate not supplied

Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon.

T-lymphocyte-mediated responses to the cellular components of blood vessels are important in rejection of allografts. The induction of cytolytic T lymphocytes (CTLs) depends on recognition of foreign class II major histocompatibility complex antigens (human HLA-DR, DC/DS, SB and others, collectively referred to as Ia) on the target cells whereas killing by CTLs usually depends on recognition of foreign class I antigens (HLA-A, B), although some alloreactive CTLs recognize foreign Ia instead of HLA-A, B (refs 5-8). The expression of Ia antigens has traditionally been regarded as restricted to immunological cell types, and the presence of class II antigen-bearing 'passenger' leukocytes in rodent organ grafts appears necessary for graft rejection. Recently, Ia antigens have been observed by immunofluorescence microscopy on human renal and dermal capillary endothelium. We have previously shown that human umbilical vein endothelial (HUVE) cells in standard culture conditions do not bear Ia antigens, but may be induced to do so by products of lectin- or alloantigen-activated T lymphocytes. Furthermore, we found that recombinant immune interferon (IFN-gamma), free of other lymphokines, is a potent inducer of Ia expression in HUVE cells. Here we report that IFN-gamma also induces Ia expression on human foreskin capillary endothelial (HFCE) cells, HUVE cells transformed by Simian virus 40 viral DNA (SV-HUVE cells) and human dermal fibroblast (HDF) cells in culture. Further, we present evidence that Ia present on HUVE cells and HDF cells can be functionally recognized by human T cells, resulting in a two-way interaction between T cells and mesenchymal cells that may be important in allograft rejection.

Cells, Cultured↗
PubMedDate not supplied

Inhibition of alloreactive cytotoxic T lymphocytes by peptides from the alpha 2 domain of HLA-A2.

Class I major histocompatibility complex (MHC) molecules function in the recognition of antigens by cytotoxic T lymphocytes (CTL). Although this biological role is firmly established and much has been learnt about their structure and polymorphic variation, little is known of the regions of class I molecules that are involved in functional interactions with components of the T-cell surface. Here we show that peptides derived from residues 98-113 of the alpha 2 domain of HLA-A2 specifically inhibit the recognition of target cells by many HLA-A2-specific CTL. In addition to identifying a region that is probably involved in binding the T-cell receptor these results raise the possibility that alloreactive CTL may recognize degraded fragments of class I histocompatibility antigens.

Amino Acid Sequence↗
PubMedDate not supplied

HLA-A2 peptides can regulate cytolysis by human allogeneic T lymphocytes.

The class-I and class-II molecules encoded by the major histocompatibility complex (MHC) are homologous proteins which allow cytotoxic and helper T cells to recognize foreign antigens. Recent studies have shown that the form of the antigen recognized by T cells is generally not a native protein but rather a short peptide fragment and that class-II molecules specifically bind antigenic peptides. Furthermore, the three-dimensional structure of the human MHC class-I molecule, HLA-A2, is consistent with a peptide-binding function for MHC class-I molecules. An outstanding question concerns the molecular nature and involvement of MHC-bound peptides in antigens recognized by alloreactive T cells. In this study the effects of peptides derived from HLA-A2 on cytolysis of alloreactive cytotoxic T cells (TC) cells are presented. Peptides can inhibit lysis by binding to the T cell or sensitize to lysis by binding an HLA-A2-related class-I molecule (HLA-Aw69) on the target cell. Thus, allospecific TC cells can recognize HLA-derived peptides in the context of the MHC.

Clone Cells↗