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C A Janeway

Publications and source records attributed to C A Janeway.

At least 235 records · Page 13Linked to original sources
PubMed1984

Cloned helper T cells can kill B lymphoma cells in the presence of specific antigen: Ia restriction and cognate vs. noncognate interactions in cytolysis.

Cloned, Lyt-1+,2-, antigen-specific, Ia-restricted T cell lines can inhibit the growth of Ia-bearing B lymphoma cells in the presence of specific antigen. This effect is due to cytolysis of the B lymphoma cells in an antigen-specific, Ia-restricted manner by the cloned T cell lines. These cloned T cell lines can also kill lipopolysaccharide-activated normal B cells, while they activate resting B cells to divide and secrete immunoglobulin and are thus helper T cells as well as cytolytic T cells. The mechanism of cytolysis was examined in detail. Killing was mediated by a nonspecific mechanism after specific stimulation of the T cells with antigen presented in the context of the appropriate Ia glycoprotein complex, possibly implying a role for a soluble mediator. This simple system involving two clonal populations allows a detailed analysis of T-B interactions. Our studies are consistent with the view that both cognate and noncognate interactions of Ia-restricted T cells with B cells are mediated by nonspecific factors. Thus, the difference between interactions that appear to be cognate and those that appear to be noncognate may be quantitative rather than qualitative. That two cloned populations of cells can show either pattern of interaction depending on T-B ratio provides strong support for this view. Finally, that cloned helper T cells can kill activated B cells in an antigen-specific fashion may provide a new mechanism of immune regulation that would be especially important in responses to self antigens in vivo.

Animals↗
PubMed1984

The expression of I-Ed molecules in F1 hybrid mice detected with antigen-specific, I-Ed-restricted cloned T-cell lines.

The expression of polymorphic determinants on I-E molecules is largely dependent on allelic variation in the E beta chain. We have previously analyzed the expression of Ek beta and Eb beta chains in F1 hybrid mice by a combination of techniques, and have shown that functional variation detected by the responsiveness of cloned T-cell lines specific for these molecules correlates well with serological determination of E beta expression. In the present study, we have extended our analysis to Ed beta expression in F1 hybrid mice. We show that Ed beta is relatively poorly expressed in three F1 combinations: H-2d X H-2b, H-2d X H-2s, and H-2d X H-2u. The former two crosses express E alpha chains from the H-2d parent only; when recombinant strains carrying Eb beta or Es beta and an active E alpha gene are used, Ed beta expression is significantly increased. On the other hand, H-2u mice synthesize E alpha chains; the poor expression of Ed beta chains in this F1 hybrid apparently reflects the strong preferential association of Eu beta chains with all E alpha molecules thus far analyzed. These results confirm that E beta chains compete for binding to E alpha chains and that preferential association of different allelic forms of E beta chains with E alpha chains is a generalized phenomenon. They also illustrate the importance of the rate of biosynthesis of Ia chains for cell-surface expression.

Alleles↗
PubMed1984

In vitro cultivation of nonlymphoid thymic cells: morphological and immunological characterization.

Nonlymphoid thymic elements play an important role in T-lymphocyte development, especially in the development of recognition of transplantation antigens (H-2 in the mouse). Understanding this process will require the isolation and characterization of these cells. A simple technique for the culture of an enriched population of murine thymic epithelium is described. The epithelial nature of these cells is evidenced by their morphology, electron microscopy, and keratin content. Readily distinguishable macrophages comprise a secondary population within these cultures. Antigens encoded in the I-A region of H-2 were found on 70% of thymic epithelial cells and H-2K on 30% of thymic epithelial cells. These antigens were generally present on distinct populations but doubly positive cells were observed. Thymic macrophages were found to have conventional receptors for the Fc fragment of immunoglobulin on their surface and could ingest antibody-coated sheep erythrocytes. Thymic epithelial cells did not have such Fc receptors. A striking observation was that thymic epithelial cells could bind and internalize autologous thymocytes. This selective thymocyte ingestion by thymic epithelium may have important implications in regard to processing of T-lymphocyte precursors.

Animals↗
PubMed1984

Distinctive immunological properties of cultured murine thymic epithelial cells.

Skin painting with chemically reactive haptens induces a hapten-specific state of hypersensitivity that is long lasting and can be transferred to unirradiated recipient mice. A similar state of hapten-specific contact sensitivity can be induced by intravenous immunization with hapten-conjugated cells. Thus far, only two cell types have been described that can perform this function: Langerhans cells of the skin, and splenic dendritic cells. All other types, coupled with hapten, induce either tolerance or a short-lived state of contact hypersensitivity that is readily suppressed, and cannot be transferred to normal recipients. In the present experiments, it was demonstrated that culture-enriched, hapten-coupled thymic epithelial cells can also induce a state of stable contact hypersensitivity identical to that induced by skin painting. This provides evidence that thymic epithelial cells have distinctive properties as antigen-presenting cells in vivo. The relationship of this finding to the postulated role of thymic epithelium in T-cell development is discussed.

Animals↗
PubMed1984

Chronic treatment with rabbit anti-mouse mu-chain antibody alters the characteristic immunoglobulin heavy-chain restriction of murine suppressor T-cell factors.

Prolonged treatment of mice, starting at birth, with rabbit anti-mouse mu-chain antibodies resulted in the elimination of immunoglobulin-bearing B cells in these animals. The ability of these animals to elicit antigen-specific delayed-type hypersensitivity or cytotoxic T-cell responses to azobenzenearsonate-coupled spleen cells was not impaired. The effect of anti-mu treatment on the restriction by immunoglobulin heavy-chain genes (Igh) of suppressor T cells was investigated. We found that first-order suppressor T-cell factor ( TsF1 ) obtained from anti-mu treated animals expresses an Igh restriction pattern distinct from that observed with TsF1 from normal untreated mice. Furthermore, TsF1 prepared from anti-mu treated animals did not express the major crossreactive idiotypic determinants normally present in TsF1 . The significance of these findings in relation to the role of immunoglobulin on the T-cell repertoire is discussed.

Animals↗
PubMed1984

Monoclonal antibodies specific for Ia glycoproteins raised by immunization with activated T cells: possible role of T cellbound Ia antigens as targets of immunoregulatory T cells.

Two monoclonal antibodies, Y-3P and Y-8P, specific for conventional mouse Ia glycoprotein antigens are described. Both were raised by repeated immunization of primed mice with activated T cells over a period of 1 yr, and both detect a new and broad public Ia specificity. Both of the antibodies react with I-A subregion-controlled A alpha:A beta complexes of all mouse strains apart from the responder strain (H-2d), as well as the equivalent of A alpha:A beta complexes in rats carrying seven independent haplotypes. These antibodies have great utility as almost universal Ia reagents. On the basis of these results, we propose that Ia antigens presented to the immune system bound to activated T cells are immunogenic, and may induce the production of Ia antibodies of novel and broad specificity. In addition, we propose that such bound Ia glycoproteins could be a target for immunoregulatory T cells, and could account for the specificity of suppression of graft-vs-host reactions and Ia-restricted helper T cells observed by others in F1 animals injected with parental T cells.

Animals↗
PubMed1984

Growth of a cloned helper T cell line induced by a monoclonal antibody specific for the antigen receptor: interleukin 1 is required for the expression of receptors for interleukin 2.

By using as an experimental system the induction of growth of a cloned, antigen:Ia-reactive helper T cell line by an antigen receptor-specific monoclonal antibody, we demonstrated that growth requires two essential co-factors, exogenously produced IL 1 and endogenously produced IL 2. The primary role of the IL 1 is in the expression of receptors on the T cell surface for IL 2, rather than for promoting the synthesis of IL 2. The use of a clone-specific activating monoclonal antibody at nanogram amounts to activate a cloned helper T cell should allow a detailed characterization of T cell activation via antigen receptor cross-linking.

Animals↗
PubMed1984

B cell-deprived mice lack functional expression of certain T suppressor cell subsets.

The generation of functionally active immunoregulatory T lymphocytes has been shown to depend upon the interaction of a number of different immune cell types during development. In order to understand and perhaps manipulate immunoregulatory T cell interactions, it is important to identify the nature and role of these cell types in the immunoregulatory T cell pathway. We have investigated the role of Ig+ B cells in the generation of suppressor T lymphocytes in the immune response to SRBC. Our approach was to suppress the expression of Ig+ B cells in experimental mice by continuously treating these animals with a rabbit anti-mu-chain antiserum. These animals were simultaneously tested for their ability to make suppressor T cell responses as measured by the ability to produce or accept SRBC-specific suppressor T cell factors. This particular approach, neonatal suppression with anti-mu-chain antibody, has been previously shown to be an effective means of depleting animals of Ig+ cells, while having little or no effect on a number of different T cell-mediated responses, including T cell mediated allograft rejection and delayed-type hypersensitivity responses in vivo as well as the generation of MLR and CTL responses to alloantigens and conventional I-A recognizing T helper cell responses in vitro. Our results indicate that anti-mu-treated mice lack the ability to produce both Ly1 and Ly2 cell-derived suppressor factors when immunized with the relevant antigen SRBC. Further, while the T cells from anti-mu-treated mice were capable of generating a T helper cell response to SRBC in vitro, these T cells no longer responded to suppressor cell signals from either the Ly1 or Ly2 T cell-derived suppressor factors. The ability to produce or accept suppressor cell signals was traced to the lack of an I-J+ Ly1 T cell absent in anti-mu-treated mice. This cell produces an I-J+ antigen nonspecific molecule which imparts Igh-V linked genetic restrictions to both the Ly1 and Ly2 T cell derived suppressor factors. The results alter our view on immune regulation by suggesting that both the induction and effector phase of suppressor T cell activity to SRBC is dependent upon an antigen nonspecific Ly1 I-J+ T cell which is distinct from the antigen recognizing I-J- T cells required for antigen-specific suppression. This I-J+ T cell, which imparts an Igh-linked restriction to the suppressor factors, is critically dependent on Ig+ B cells to reach a functionally active state.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Antigen-dependent selection of B lymphoma cells varying in Ia density by cloned antigen-specific L3T4a+ T cells: a possible in vitro model for B cell adaptive differentiation.

The study of Ia glycoprotein antigens has focused on qualitative differences: allelic polymorphism, mutants and differences between the I-A and I-E molecules. However, as the only known function of Ia glycoproteins is in the presentation of antigen to syngeneic T cells, quantitative rather than qualitative variation might be expected to be the critical variable in cell interactions. To examine the role of Ia antigen density in T-B interactions, we have used a novel system involving the lysis of B lymphoma cells in the presence of protein antigen and cloned, antigen plus Ia specific helper T cells. The B lymphoma cells that survive this interaction can be recovered, and both their level of Ia antigen and their susceptibility to antigen-specific lysis determined. We have found that B lymphoma cells surviving lysis express less cell surface Ia antigen than the parent B lymphoma line, and are correspondingly more difficult to lyse. Several properties of this system are of interest. First, Ia antigens the genes for which are on the same chromosome as that recognized by the selecting cloned T cell are expressed at quantitatively similar levels, while those on a polymorphic homologous chromosome are not. Thus, in hybrid B cells. Ia antigen expression is regulated in cis and not trans. Second, alteration in Ia antigen expression is stable in continuous culture. Third, the variants pre-exist in the population of B lymphoma cells. Thus, the role of the T cell is to select pre-existing variants, not to generate variation. Fourth, the amount of protein antigen required to get lysis of the variant and parent lines to equivalent levels is reciprocally related to the mean cell surface density of the Ia antigen recognized by the test clone, suggesting that antigen and Ia molecules form complexes, and that complex formation is governed by the law of mass action. And finally, since the lytic cloned cells appear to effect lysis by release of a non-specific lytic intermediate, while the effect on the B cells appears to be cognate, these data are consistent with others suggesting that all T-B interactions require T cell recognition of antigen-Ia complexes at the B cell surface, but are mediated by release of nonspecific T cell factors. These results suggest that B cell Ia antigen expression is quite stable, and that in F1 B cells, the expression of the two alleles is independently regulated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells.

Two antisera and a monoclonal antibody raised in BALB.K mice against cloned, major histocompatibility complex (MHC)-restricted, antigen-specific helper T cell lines are described. These antibodies are specific for individual cloned T cell lines and are potent inducers of T cell proliferation. The induction of T cell proliferation by these antibodies requires the presence of an adherent accessory cell. There is no H-2 restriction between this accessory cell and the cloned T cell, nor is this antibody-induced proliferation blocked by a monoclonal anti-Fc receptor antibody. The requirement for an accessory cell, however, is eliminated in the presence of an IL-1- or IL-2-rich supernatant. Thus this system allows the analysis of helper T cell activation with only a single cell type present. Anti-T cell sera also induce T cell-dependent B cell proliferation and immunoglobulin secretion. The induction of T cell-dependent B cell activation by these sera does not require H-2-matched T cells and B cells. The specificity of these antibodies and their ability to stimulate cloned helper T cells in the absence of antigen and antigen-presenting cells strongly suggest that these antibodies are directed against antigen and/or Ia recognition sites on the T cell.

Animals↗
PubMed1983

Affinity-purified antigen-specific products produced by T cells share epitopes recognized by heterologous antisera raised against several different antigen-specific products from T cells.

Heterologous antisera to murine or rat T-cell antigen-binding molecules (T-ABM) were raised in rabbits or sheep. The T-ABM used for immunization were purified by affinity for antigen and did not bear known immunoglobulin isotypes. T-ABM and anti-T-ABM were raised in three separate laboratories. Antisera to T-ABM were exchanged and tested for binding to T-ABM in three separate laboratories. Thus antisera to at least three distinct T-ABM were tested directly for binding to T-ABM or by adsorption of biological activity. Rabbit antisera to murine trinitrophenol (TNP)-specific T-ABM or rat AgB-specific T-ABM bound both murine or rat T-ABM, indicating evolutionary conservation of T-ABM. Similar results were found with sheep antisera to murine T-ABM. In addition, all heterologous anti-T-ABM antisera used bound murine T-ABM specific for TNP, 4-hydroxy-3-nitrophenyl acetate (NP), SRBC, or T-cell membrane proteins with similar structure. Thus, there is a commonality of antigenic determinants between various T-ABM and T-cell membrane homologues which may be T-cell surface receptors for foreign antigen.

Animals↗
PubMed1983

Use of anti-idiotype immunosorbents to isolate circulating antigen-specific T cell-derived molecules from hyperimmune sera.

We immunized four different sheep with antigen-binding material found in the serum of BALB/c mice 4 days after primary immunization with sheep erythrocytes (SRBC). The resultant antibodies made by the sheep contained a specificity(ies) that appeared to react with a dominant idiotype present on SRBC-specific Lyt-2+ T cells. The antiserum made by the sheep markedly inhibited the formation of antigen-specific rosettes by SRBC educated T cells but did not inhibit T cells educated to other heterologous erythrocytes from forming crossreacting rosettes with SRBC or specific rosettes with the homologous erythrocytes. The "anti-Id serum" was depleted of all activity against known immunoglobulin isotypes and light chains and then was used to isolate antigen-binding molecules from mice that were hyperimmunized with SRBC. The ShId+ material so isolated could be divided into two main groups--one that expressed immunoglobulin determinants, and one that did not. The former represented 15-25% of the ShId+ protein isolated and comprised a minority of the anti-SRBC antibody in the anti-SRBC serum; the latter group of proteins bound sheep glycophorin specifically and expressed constant region determinants found on a number of other antigen-specific T cell factors. These experiments suggest that antigen-binding molecules made by T cells display much less heterogeneity than do antibodies and also show that the serum of hyperimmune mice contains significant amounts of T cell-derived antigen-specific immunoregulatory molecules.

Animals↗
PubMed1983

A cloned, antigen-specific, Ia-restricted Lyt-1+,2- T cell with suppressive activity.

The correlation between cell surface antigen phenotype and function is one of the cornerstones of modern cellular and clinical immunology. It is based on the collective experience of many investigators examining populations of T cells. The availability of cloned lines of T cells now allows us to ask whether all cells sharing cell surface antigen phenotype are functionally equivalent. We have examined a large number of antigen-specific, self-Ia recognizing, cloned Lyt-1+,2- T cell lines for their ability to help B cells proliferate and secrete antibody in response to antigen. All of these lines induced antigen-specific, Ia-restricted B cell proliferation. One line did not induce antibody secretion. This line, indeed suppressed the plaque-forming cell response of B cells helped by any of the other cloned T cell lines tested. Suppression in this system had all the characteristics of classical T cell help, apart from the ultimate outcome. That is, the suppressor cell acted upon the B cell in a manner that was antigen-specific, Ia-restricted, and required hapten-carrier linkage. We interpret our results as supporting the basic paradigm of an association of cell surface antigen phenotype with function, with an important proviso. Not all Ly1, Ia-restricted T cells may be capable of helper function, and some in fact may be suppressive. Experimental conditions favoring the generation of such cells, or disease states in which such cells reside within the Ly1 or T4+ subset, may give rise to disparities between phenotype and function similar to that observed here at the clonal level.(ABSTRACT TRUNCATED AT 250 WORDS)

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