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E Heber-Katz

Publications and source records attributed to E Heber-Katz.

66 records · Page 4Linked to original sources
PubMed1983

Major histocompatibility complex-controlled, antigen-presenting cell-expressed specificity of T cell antigen recognition. Identification of a site of interaction and its relationship to Ir genes.

In previous work (5,6), we have reported studies on a T lymphocyte hybridoma clone and the peritoneal exudate T cells (PETLES) from B10.A(5R) mice primed with the cytochrome c carboxyl terminal peptide (residues 81-103) of the tobacco horn worm moth (Manducca sextus). As expected, since B10.A(5R) is a low responder to pigeon fragment 81-104, it was found that the B10.A(5R) lymphocytes were unable to respond to the pigeon cytochrome c 81-104 fragment presented on syngeneic B10.A(5R) antigen-presenting cells (APC). However, these same T lymphocytes did respond to the pigeon fragment when presented on B10.A APC. Thus, some structural difference between the pigeon and moth peptides had prevented B10.A(5R) APC from effectively presenting the pigeon fragment to moth-primed B10.A(5R) lymphocytes. This structural difference was found to be the deletion of an alanine at position -103 (Ala103) from the pigeon sequence in the moth peptide. Two additional T cell specificities were created by changing residue-99. These T cell populations from the B10.A(5R) showed an identical dependence on the Ala103 deletion when B10.A and B10.A(5R) APC were compared. The relationship of APC-expressed antigen specificity and MHC-linked immune responsiveness differences was also examined. The B10.A(5R) was found to be a high responder to each of three peptides that lack Ala103 but not to the Ala103-containing analogues. B10.A mice, in contrast, respond to both types of peptides. Utilizing allogeneic antigen-presentation to B10.A PETLES by pulsed APC, it was shown that the poor response of the B10.A(5R) to the Ala103-containing peptides was, in two of three cases, not associated with any differences in T cell repertoires but due to two different APC capabilities of B10.A and B10.A(5R). The exception apparently represents a case of T cell repertoire polymorphism between B10.A and B10.A(5R) that can also affect immune responsiveness.

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PubMed1983

The Ia molecule of the antigen-presenting cell plays a critical role in immune response gene regulation of T cell activation.

It is now clear that MHC-encoded molecules influence the immune response by their effects on T cell specificity. However, the mechanism(s) by which this occurs in an antigen-specific manner is not clear. Two broad categories of models have been proposed. One postulates that Ia molecules influence the T cell repertoire during ontogeny and that the clones of T cells capable of recognizing the antigen in association with the nonresponder Ia molecule are deleted or are never assembled. The other postulates that Ia molecules influence the immune response during T cell activation and that the clones of T cells capable of recognizing the antigen in association with the nonresponder Ia molecule are not stimulated because this Ia molecule does not bind or interact well with the antigen. Recent experiments by several laboratories have identified allogeneic T cell clones and populations capable of responding to an antigen in association with nonresponder Ia molecules. This result suggested that nonresponder Ia molecules are capable of interacting with antigen in a functional manner. Therefore it was inferred that Ir gene defects must lie in the T cell repertoire. However, we have recently discovered several mouse T cell clones whose characteristics suggest that this conclusion might not describe the complete picture. These clones have the unusual property of recognizing moth cytochrome c in association with either B10.A or B10.A(5R) Ia molecules, but they recognize pigeon cytochrome c only in associated with B10.A Ia molecules. Thus, the Ia-molecule-antigen interaction appears to be able to affect the fine specificity of the T cell activation process. Interestingly, the failure to respond to pigeon cytochrome c in association with B10.A(5R) Ia molecules correlates with the Ir gene control of the response to this antigen since the B10.A(5R) strain is a nonresponder to pigeon cytochrome c whereas the B10.A strain is a responder. The question we wished to address in this paper was whether the clones we had identified were representative of the T cell repertoires of both strains. If so, this would allow us to conclude that Ia molecule-antigen interactions during T cell activation could account for Ir gene control in certain situations. To answer the experimental question, we first examined several more T cell clones from [B10.A x B10.A(5R)]F1 and B10.A(5R) mice to solidify our previous findings. Then we turned to populations of T cells to determine if these findings could be generalized.(ABSTRACT TRUNCATED AT 400 WORDS)

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PubMed1982

Contribution of antigen-presenting cell major histocompatibility complex gene products to the specificity of antigen-induced T cell activation.

Previous studies from our laboratory showed that B 10.A mice are high responders to pigeon cytochrome c fragment 81-104, whereas'B 10.A(5R) mice are low responders. In the present studies, the C-terminal cyanogen bromide cleavage fragment and homologous synthetic peptides of tobacco horn worm moth cytochrome c were shown to be immunogenic in both B10.A and B10.A(5R) mice. These strains, however, showed different patterns of cross-reactivity when immune lymph node T cells were stimulated with cytochrome c fragments from other species. To examine the two patterns of responsiveness at a clonal level, cytochrome c fragment-specific T cell hybridomas were made and found to secrete interleukin 2 in response to antigen. The patterns of cross- reactivity of these B 10.A and B 10.A(5R) clones were similar to that seen in the whole lymph node population. Surprisingly, when these clones were tested for major histocompatibility complex (MHC)-restricted antigen recognition, they were all found to respond to antigen with both B10.A and B10.A(5R) antigen-presenting cells (APC). Furthermore, the cross-reactivity pattern appeared to be largely determined by the genotype of the APC, not the genotype of the T cell clone. That is, a given T cell clone displayed a different fine specificity when assayed with B10.A or B10.A(5R) APC. This observation indicates that the APC MHC gene product and antigen interact during the stimulation of the T cell response and that as a consequence the specificity of antigen-induced T cell activation is influenced by these MHC gene products. (During the preparation of this manuscript it has come to our attention that results similar to our own, concerning the fine specificity of cytotoxic T cell clones, have been obtained by Dr. T. R. Hunig and Dr. M. J. Bevan, Massachusetts Institute of Technology, Boston, MA. T. R. Hunig and M. J. Bevan. 1981. Specificity of T-cell clones illustrates altered self hypothesis. Nature. 294:460.)

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PubMed1982

Use of a solid-phase 3H-radioimmunoassay for the measurement of immunoglobulin produced in short-term cultures of antibody-secreting cells.

A slid-phase radioimmunoassay (RIA) for assaying immunoglobulin produced from antibody-secreting myeloma, hybridoma and immune spleen cells is described. Specific antibody is detected by culturing antibody-producing cells on antigen-coated flexible polyvinylchloride microtiter wells, washing away the cells, and measuring the bound specific antibody with tritiated affinity-purified anti-isotype reagents. Antibody produced from 10(3) myeloma cells can be detected with as little as 4 h of incubation. With 24-48 h of incubation, antibody from as few as approximately 3-15 myeloma, hybridoma or immune spleen plaque-forming cells (PFC) can be detected. This culture-well RIA has certain distinct advantages over the hemolytic PFC assay and RIA assays in which antibody in culture supernatants is measured.

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PubMed1982

The fine specificity of antigen and Ia determinant recognition by T cell hybridoma clones specific for pigeon cytochrome c.

The activation of proliferative T lymphocytes normally involves the simultaneous recognition of a particular foreign antigen and a particular Ia molecule on the surface of antigen-presenting cells, the phenomenon of major histocompatibility complex (MHC) restriction. An analysis of T cell clones specific for pigeon cytochrome c, from B10.A and B10.S(9R) strains of mice, revealed the unusual finding that several of the clones could respond to antigen in association with Ia molecules from either strain. Using these cross-reactive clones, we performed experiments which demonstrated that both the Ia molecule and the T cell receptor contribute to the specificity of antigen recognition; however, MHC-linked low responsiveness to tuna cytochrome c (an immune response gene defect) could not be attributed solely to the efficacy with which the Ia molecules associated with the antigen. These results imply that antigen and Ia molecules are not recognized independently, but must interact at least during the process of T cell activation.

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PubMed1981

Idiotype-anti-idiotype regulation. I. Immunization with a levan-binding myeloma protein leads to the appearance of auto-anti-(anti-idiotype) antibodies and to the activation of silent clones.

BALB/c mice immunized multiple times with ABPC48 (A48 or Ab1), a BALB/c bacterial levan (BL)-binding myeloma proteins, produce anti-Ab1 antibodies (Ab2). Immunization with only tow doses of AB1 often leads to the production of anti (antiA48) (Ab3) as does immunization with hemocyanin conjugates of Ab2. Finally, immunization with hemocyanin conjugates of Abf3 leads to the production of anti- (anti-[anti-A48]) (Ab4). Normal BALB/c mice immunized with BL produce an anti BL antibody response containing no detectable Ab1 idiotype (Id)-bearing molecules. Mice producing Ab3 express substantial amounts of Ab1 Id in their anti-BL response whereas mice producing Ab2 and Ab4 show a generalized inhibition in their anti BL response. These results indicate that states of immunity within an idiotypic chain may have marked effect on antibody responses to the antigen (i.e., BL) which is the putative initiator of the chain. Strikingly, the chain itself has an interesting feature. That is, Ab3 and Ab1 share a cross-reactive Id in that both are bound by Ab4 and Ab2. We propose a model of Id-anti-Id systems to explain this unexpected result. This is based on the concept of regulatory idiotopes on Ab1 molecules which initiate Ab2 (anti-idiotope) responses. In contrast, Ab2 molecules generally fail to initiate anti-Ab2 Id responses eigher because any individual idiotope is present at very low concentration or because Ab2 molecules tend to lack regulatory idiotopes. Thus, Ab2 molecules immunize syngeneic animals because they interact with cells bearing Ab1 like regulatory idiotopes. Thus, Ab3 will share regulatory idiotopes with Ab1. Ab4 and Ab2 will share the ability to bind the Ab1-like regulatory idiotope.

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PubMed1980

TNP-coupled membranes stimulate T cell proliferation via the macrophage.

TNP-coupled membranes derived from guinea pig m phi were capable of inducing both primary and secondary antigen-specific T cell proliferative responses; however, effective stimulation by hapten-coupled membranes required the presence of unmodified m phi. A genetic analysis demonstrated that the Ia antigens of the unmodified m phi rather than the Ia antigens borne on the TNP-coupled membranes determined the histocompatibility restrictions on m phi T cell interaction.

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PubMed1976

Sheep red blood cell-specific helper activity in rat thoracic duct lymphocyte populations positively selected for reactivity to specific strong histocompatibility alloantigens.

These studies show that positively selected T-cell populations, having enriched reactivity in the mixed lymphocyte interaction and the graft-versus-host reaction to strong alloantigens of a chosen major histocompatibility complex haplotype, also possess helper activity which is quantitatively normal in the generation of primary antibody responses to sheep red blood cells in vitro. Such positively selected populations give a linear dose plaque-forming cells response curve indistinguishable from that seen with normal unselected T-cell populations. These findings imply that T cells reactive to histocompatibility antigens also react to conventional antigens, and the possibility is raised that they may do so by some recognition mechanism involving multiple specificities.

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PubMed1975

Collaboration of allogeneic T and B lymphocytes in the primary antibody response to sheep erythrocytes in vitro.

This study provides a direct quantitative comparison of the helper effects of allogeneic and syngeneic rat T cells in the production of direct SRBC plaque-forming cell (PFC) responses by B cells in culture. In syngeneic T-B combinations, log-log plots of the number of PFC generated after 5.5 days in culture vs. the number of T cells employed as helpers showed a linear response between 10(4) and 2.5 times 10(5) T cells added. Allogeneic T-B combinations, in which the T cells possess the capacity for reactivity to major alloantigens of the B-cell donor, showed a different dose/response relationship in which PFC responses were decreased at high T/B ratios and augmented at low T/B rations. In this system responses were detected with as few as 10(3) allogeneic T cells. Use of negatively selected allogeneic T populations, specifically depleted of mixed lymphocyte interaction (MLI) and graft-vs-host reactivity for B-cell alloantigens, as helpers gave dose/response curves quantitatively identical to responses with syngeneic T-B combinations and also with F1 T-cell parental B-cell combinations. These data indicate that rat T and B cells need not share a major histocompatibility complex haplotype in order to collaborate effectively in a primary direct PFC response to SRBC in culture. In addition, the PFC response required the combinaed presence of T and B cells as well as antigen in the cultures, a finding consistent with the two signal model of B-cell activation. Finally, the dose/response data obtained suggest the possibility that although SRBC antigen is required in the cultures helper activity with low numbers of normal allogeneic T cells may not depend on T cells having specificity for this antigen.

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