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Biomedical subjects

J A Bluestone

Publications and source records attributed to J A Bluestone.

266 records · Page 15Linked to original sources
PubMed1979

Suppression of the immune response in tumor-bearing mice. I. Response to virus-producing tumor cells and non-virus-producing tumor cells.

Spleen cells from mice inoculated with syngeneic murine sarcoma virus (MuSV)-transformed tumor cells suppressed the mixed leukocyte reaction. Mice inoculated with virus-producing tumor cells demonstrated two types of suppression. First, an early suppression was shown to be mediated by an adherent suppressor T-cell on the basis of its sensitivity to Thy 1.2 antiserum plus complement and the absence of the early suppression in T-cell-deficient nude mice. This suppression may have been induced in response to viral antigens associated with cell surface antigens (modified self-antigens) or viremia, because it was not induced by a non-virus-producing tumor cell line. Second, a late suppression was also seen in tumor-bearing BALB/c mice. This suppression was shown to be T-cell-independent by its presence in nude mice and by its resistance to gamma-irradiation and Thy 1.2 antiserum plus complement. In addition, the late suppression was present in mice inoculated with a nonproducer clone of MuSV-transformed cells. This finding suggests that viral antigens and/or viremia is not required for induction of the late suppression.

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PubMed1979

Suppression of the immune response in tumor-bearing mice. II. Characterization of adherent suppressor cells.

Adherent spleen cells from late (greater than or equal to 18 days post inoculation) tumor-bearing BALB/c mice suppressed lymphoproliferative and effector immunity as evaluated by the mixed leukocyte culture and cell-mediated lympholysis assays. Procedures that eliminated T-cells or B-cells while enriching for macrophage populations significantly augmented the suppression, whereas removal of phagocytic and adherent cells abrogated the suppressive effect. We concluded that the cells responsible for suppression of cell-mediated immune responses in late tumor-bearing mice were of the monocyte-macrophage series. Furthermore, the suppressive influence was not due merely to the increased number of macrophages in tumor-bearing animals. Experiments clearly showed that the splenic macrophages, even at low concentrations, demonstrated a suppressive function.

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PubMedDate not supplied

Specific targeting of cytotoxic T cells by anti-T3 linked to anti-target cell antibody.

The specificity of cytotoxic T lymphocytes (Tc) cells is conferred by an antigen-specific receptor, Ti, which in humans is physically associated with an invariant cell-surface glycoprotein, T3. Monoclonal antibodies specific for either T3 and Ti are able to elicit a variety of T-cell responses such as lymphokine production, mitogenesis and cytotoxicity. For example, human Tc cells lyse anti-T3-expressing hybridoma cells, but not cells of other specificity, presumably because anti-T3 on the hybridoma cells binds to T3 on the Tc cells and triggers lysis. Here, we have adapted approaches used in a different cytotoxic effector system, antibody-dependent cellular cytotoxicity (ADCC), to alter the specificity of Tc cell. Studies of ADCC showed that heteroaggregates containing anti-Fc receptor (Fc gamma R) antibody cross-linked to a second antibody bind to Fc gamma R on ADCC effectors and cause them to kill target cells bearing antigen recognized by the second antibody. The present studies use anti-T3-containing heteroaggregates to re-target human Tc cells to cells for which we have appropriate antibodies, including xenogeneic tumour cells and chicken erythrocytes. These results extend previous observations on the role of T3 in triggering cytotoxicity and suggest that effector cell re-targeting could be used for in vivo treatment of neoplasms and other pathogens that express distinctive surface antigens.

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PubMedDate not supplied

Differential expression of two distinct T-cell receptors during thymocyte development.

The product of the T-cell receptor (TCR) gamma-gene has recently been found to be expressed on a subset of both peripheral cells and thymocytes. As an initial approach to understanding the role of this gamma-chain of TCR (TCR gamma) in T-cell development, we have studied the ontogeny of TCR expression at the protein level in the developing murine thymus. We show here that the first T3-associated TCR to be expressed in the developing thymus is a disulphide-linked heterodimer composed of a gamma-chain of relative molecular mass 35,000 (Mr 35K) and a 45K partner (termed TCR delta). This TCR gamma delta is first detected approximately two days before the appearance of cell-surface TCR alpha beta heterodimers. We report that N-glycosidase digestions reveal that all of the gamma-protein expressed on fetal thymocytes, as in adult CD4-8-(L3T4-, Lyt2-) thymocytes, bear N-linked carbohydrate side chains. The major gamma-gene transcribed in mature, alpha beta-bearing T cells (V gamma 1.2C gamma 2)encodes no N-linked glycosylation site so these results suggest that the fetal gamma delta receptor defines a distinct T-cell lineage whose development in the thymus precedes classical alpha beta-bearing cells.

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PubMedDate not supplied

Characterization of murine thymocytes with CD3-associated T-cell receptor structures.

The thymus is the major site for T-cell receptor (TCR) gene rearrangement and T-cell maturation. The specific antigen recognition structure (TCR) on murine T cells has been shown to be dependent on a polymorphic set of disulphide-linked heterodimers, containing two integral membrane glycoprotein chains, TCR alpha and TCR beta, expressed in non-covalent association with an invariant complex of proteins, CD3 (T3). Recently, a novel TCR/CD3 complex, that includes the product of the TCR gamma gene, has been identified on a subset of both peripheral cells and thymocytes. Here we examine the expression of TCR/CD3 complexes in fetal ontogeny and in the adult thymus. The results demonstrate that CD3+4-8-(T3+,L3T4-,Lyt2-)cells are detected in day-15 fetal thymi, throughout fetal development and in adult thymus. In situ hybridization studies indicate that these early CD3+ cells express high levels of TCR gamma-specific RNA, low levels of TCR beta-specific RNA and no detectable TCR alpha-specific RNA. Day-16 CD3+,4-,8- fetal thymocytes can be activated to proliferate and demonstrate cytolytic activity when cultured in the presence of anti-CD3 monoclonal antibodies and interleukin-2 (IL-2). These results suggest that CD3-bearing cells, present early in thymic ontogeny, express a functional TCR and may, therefore, be important in repertoire development.

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PubMedDate not supplied

Major histocompatibility complex-linked specificity of gamma delta receptor-bearing T lymphocytes.

Several recent studies have identified a distinct subset of CD3(T3)+CD4-CD8-T lymphocytes that express a CD3-associated heterodimer made up of the protein encoded by the T-cell receptor (TCR) gamma-gene and a second glycoprotein termed TCR delta (refs 1-4). TCR gamma delta is expressed on CD3+ thymocytes during fetal ontogeny before the appearance of TCR alpha-beta (alpha beta) (refs 5-7), on CD3+CD4-CD8- adult thymocytes, and on a subset (1-10%) of CD3+ cells in adult peripheral lymphoid organs and the peripheral blood. TCR gamma delta-expressing T cells probably represent a distinct mature T-cell lineage with the capacity to proliferate in response to receptor-mediated signals, and to display non-major histocompatibility complex (MHC)-restricted cytolysis. Critical to understanding the function of this T-cell subset is the identification of the ligand(s) recognized by TCR gamma delta. Here we describe an alloreactive CD3+CD4-CD8-TCR gamma delta-expressing, TCR alpha beta-negative, T-cell line that manifests MHC-linked recognition specificity for both proliferation and cytotoxicity. Our results suggest that T cells expressing TCR gamma delta are capable of self-non-self MHC discrimination and that they can undergo MHC-influenced selection during differentiation like TCR alpha beta-expressing T cells.

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PubMedDate not supplied

Serological analysis of H-2 mutations using monoclonal antibodies.

Nine H-2Kb and H-2Db mutants were examined for serological differences from the wild type C57BL/6 using a panel of monoclonal antibodies (mAbs). Several differences (between the Kb mutants) were established with these mAbs. The bm3 and bm11 mutants could be distinguished serologically even though they have very similar amino acid changes. Conversely, the bm 1 and bm 10 mice, which differ in their sites of Kb mutation, express a common serological mutation, suggesting that tertiary conformation is involved in antibody binding. Both bm13 and bm14 (H-2Db mutants) exhibited profound serological alterations in H-2Db molecules when tested with mAbs that bind determinants mapping to both the NC1 and C2M domains of the Db molecule. In addition, bm13 showed altered binding of two anti-H-2Kb monoclonals.

Amino Acid Sequence↗
PubMedDate not supplied

Differential effects of T cell receptor ligation of TCR gamma delta thymocyte development in fetal thymic organ culture.

Fetal thymus organ culture system (FTOC), a well-known model used for the study of TCR alpha beta development, was employed to study TCR gamma delta cell development. It was found that different waves of TCR gamma delta cells develop from precursors within the fetal thymi at the time in vitro culture. Subsets of fetal thymocytes were analyzed by flow cytometry and 2-D gel biochemical analysis was performed. After 5 days in FTOC, V gamma 3+ and V gamma 2+ cells were dominant. By day 12 FTOC, the absolute number of V gamma 3+ cells decreased while V gamma 2+ and V gamma 4+ cells became dominant. These observations suggest that the thymic micro-environment affects the thymic waves of TCR gamma delta subsets. Furthermore, the effect of TCR/antigen interaction in the development of TCR gamma delta cells was examined with anti-TCR mAbs added into the FTOC. Anti-CD3 mAb added to day 5 and day 12 FTOC inhibited TCR gamma delta development, especially V gamma 4+ cells. On the other hand, V gamma 2+ cells were relatively resistant to the addition of anti-TCR mAb. The reduction of TCR gamma delta+ thymocytes was not due to the modulation of TCR molecules and could be reversed by Cyclosporin A (CsA). These results suggest that TCR ligation negatively regulates the development of TCR gamma delta cells in a V gamma-specific manner.

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