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2. Distinct functions of tapasin revealed by polymorphism in MHC class I peptide loading.
- Author
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Peh CA, Laham N, Burrows SR, Zhu Y, and McCluskey J
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP-Binding Cassette Transporters metabolism, Adjuvants, Immunologic physiology, Alleles, Animals, Antigen Presentation genetics, Antiporters genetics, Antiporters metabolism, Cell Line, Transformed, Cell Membrane genetics, Cell Membrane immunology, Cell Membrane metabolism, HLA-B Antigens biosynthesis, HLA-B Antigens genetics, HLA-B Antigens immunology, HLA-B Antigens metabolism, HLA-B44 Antigen, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I immunology, Humans, Immunoglobulins genetics, Immunoglobulins metabolism, Membrane Transport Proteins, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Solubility, Transfection, Tumor Cells, Cultured, Antiporters physiology, Histocompatibility Antigens Class I metabolism, Immunoglobulins physiology, Peptides immunology, Peptides metabolism, Polymorphism, Genetic immunology
- Abstract
Peptide assembly with class I molecules is orchestrated by multiple chaperones including tapasin, which bridges class I molecules with the TAP and is critical for efficient Ag presentation. In this paper, we show that, although constitutive levels of endogenous murine tapasin apparently are sufficient to form stable and long-lived complexes between the human HLA-B*4402 (B*4402) and mouse TAP proteins, this does not result in normal peptide loading and surface expression of B*4402 molecules on mouse APC. However, increased expression of murine tapasin, but not of the human TAP proteins, does restore normal cell surface expression of B*4402 and efficient presentation of viral Ags to CTL. High levels of soluble murine tapasin, which do not bridge TAP and class I molecules, still restore normal surface expression of B*4402 in the tapasin-deficient human cell line 721.220. These findings indicate distinct roles for tapasin in class I peptide loading. First, tapasin-mediated bridging of TAP-class I complexes, which despite being conserved across the human-mouse species barrier, is not necessarily sufficient for peptide loading. Second, tapasin mediates a function which probably involves stabilization of empty class I molecules and which is sensitive to structural compatibility of components within the loading complex. These discrete functions of tapasin predict limitations to the study of HLA molecules across some polymorphic and species barriers.
- Published
- 2000
- Full Text
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3. Characterization of anti-single-stranded DNA B cells in a non-autoimmune background.
- Author
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Nguyen KA, Mandik L, Bui A, Kavaler J, Norvell A, Monroe JG, Roark JH, and Erikson J
- Subjects
- Animals, Autoimmunity, Gene Transfer Techniques, Immunoglobulin M immunology, Immunoglobulins genetics, Mice, Mice, Inbred BALB C, Mice, Transgenic, Antibodies, Antinuclear immunology, B-Lymphocytes immunology, DNA, Single-Stranded immunology, Immunoglobulins immunology
- Abstract
Anti-DNA Abs are prevalent in the serum of systemic lupus erythematosus (SLE) patients and in the MRL-lpr/lpr mouse model of SLE, but are generally absent in normal individuals. We have studied the regulation of anti-ssDNA B cells in a non-autoimmune (BALB/c) background by using Ig transgenes (Tgs) encoding anti-DNA Abs. In one case, they are present with other non-DNA-binding B cells (the VH3H9 Tg with endogenous light chains); in the other, they are present as an essentially monospecific population (VH3H9/Vkappa8). We have previously observed that serum anti-ssDNA levels in these Tg mice were no higher than those of non-Tg mice, despite the fact that anti-ssDNA B cells dominate the peripheral B cell repertoire. These results suggested that the anti-ssDNA Tg B cells present are functionally inactivated. In this paper, we isolate B cells from VH3H9/Vkappa8 Tg mice to show that this is indeed the case and go on to further define this state. We demonstrate that VH3H9/Vkappa8 Tg B cells have diminished Ig secretion in response to both T-independent and T-dependent stimuli compared with non-Tg controls. VH3H9/Vkappa8 Tg B cells also show suboptimal proliferation in response to anti-IgM F(ab)'2 fragments and LPS, and are phenotypically distinct in expressing decreased total surface Ig. Despite their functional defects, however, VH3H9/Vkappa8 Tg B cells have an in vivo turnover rate comparable to non-Tg B cells, suggesting that they are long lived.
- Published
- 1997
4. Leukotriene C4 produced by a human T-T hybridoma suppresses Ig production by human lymphocytes.
- Author
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Ambrus JL Jr, Jurgensen CH, Witzel NL, Lewis RA, Butler JL, and Fauci AS
- Subjects
- Antigens, Differentiation, T-Lymphocyte analysis, Cell-Free System, Flow Cytometry, Humans, Hybridomas analysis, Hybridomas immunology, Immunosuppressive Agents analysis, Immunosuppressive Agents biosynthesis, SRS-A isolation & purification, SRS-A physiology, T-Lymphocytes analysis, T-Lymphocytes immunology, Antibody-Producing Cells metabolism, Hybridomas metabolism, Immunoglobulins biosynthesis, Immunosuppressive Agents physiology, SRS-A biosynthesis, T-Lymphocytes metabolism
- Abstract
Multiple signals are involved in the regulation of Ig production by human B lymphocytes. Leukotrienes, especially LTB4, have been shown to inhibit Ig production by increasing the number and function of suppressor lymphocytes. Production of leukotrienes has been demonstrated by mast cells, basophils, eosinophils, polymorphonuclear leukocytes, monocytes, and macrophages. In this paper we demonstrate that a human T-T hybridoma grown at 5 x 10(5) cells/ml constitutively produces 5 ng/ml of LTC4. Furthermore, we demonstrate that either the supernatant from this hybridoma containing 0.5 to 10 ng/ml LTC4 or purified LTC4 in the range of 0.5 to 5 ng/ml can suppress 50 to 70% of Ig production by unfractionated human mononuclear cells, by normal human cells stimulated with Staphylococcus aureus Cowan I and B cell differentiation factors, and by the EBV-transformed B cell line SKW.6 in the presence of B cell differentiation factors. Thus, LTC4 can have direct effects on B cells and may have a role in normal B cell regulation.
- Published
- 1988
5. Regulation of immunoglobulin synthesis by human T cell subsets as defined by anti-D44 monoclonal antibody within the CD4+ and CD8+ subpopulations.
- Author
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Calvo CF, Bernard A, Huet S, Leroy E, Boumsell L, and Senik A
- Subjects
- Antigen-Antibody Reactions, Antigens, Differentiation, T-Lymphocyte, B-Lymphocytes immunology, B-Lymphocytes metabolism, Humans, Lymphocyte Activation, Lymphocyte Cooperation, Phenotype, Pokeweed Mitogens pharmacology, T-Lymphocytes classification, T-Lymphocytes, Helper-Inducer immunology, Antibodies, Monoclonal immunology, Antigens, Surface immunology, Immunoglobulins biosynthesis, T-Lymphocytes immunology
- Abstract
In our previous paper, we demonstrated that anti-D44 MAb can, in the presence of complement, eliminate all the allocytotoxicity generated during a mixed lymphocyte reaction without affecting the alloproliferative response. As approximately 70% of CD4+ cells and 30% of CD8+ will be stained with anti-D44 MAb, we researched the functional role of the D44+ and D44- cells in each of these T cell subsets in the PWM-induced antibody response. We found that most of the helper activity for immunoglobulin (Ig) synthesis was mediated by CD4+ D44+ lymphocytes and that virtually all the suppressive activity was mediated by CD8+ D44- lymphocytes. Surprisingly enough, we noticed that the low level of Ig synthesis induced in B cells by CD4+ D44- lymphocytes could be strongly amplified by the addition of radiosensitive CD8+ lymphocytes, suggesting coexisting opposite immunoregulatory functions within the CD8+ T cell subset. These results, together with previous data, indicate that anti-D44 MAb subdivides T cells into subpopulations with distinct functional repertoires: a CD4+ D44+ helper subpopulation, a CD8+ D44+ cytotoxic subpopulation, and a CD8+ D44- suppressor subpopulation.
- Published
- 1986
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