The targeting of effector molecules in the immune system.
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Animals↗
Biomedical subjects
C A Janeway
Publications and source records attributed to C A Janeway.
Immune serum from mice contact-sensitized with picryl chloride contains an antigen-specific T cell factor that transfers immediate cutaneous reactivity.
This report describes an activity in serum from mice that were contact-sensitized with picryl chloride (PCl) 1 to 4 days earlier. Immune serum, when given i.v., transfers the ability to elicit an immediate hypersensitivity-like ear swelling reaction in naive recipients following local challenge with PCl. This serum activity is due to an antigen-binding T cell factor that shares some properties with IgE antibody. The activity is antigen specific, and due to an antigen-binding moiety that is heat labile (56 degrees C, 4 h). However, unlike IgE antibody the serum activity is resistant to reduction and alkylation, and is retained by columns of Sepharose beads coupled with polyclonal or monoclonal antibodies that react with antigen-specific T cell factors from other systems. These columns did not retain IgE antibody activity in our experiments. Importantly, the serum activity was not retained by columns linked with antibodies directed to mouse immunoglobulins, which do retain IgE activity. We conclude from these data that the activity in PCl immune serum is not caused by IgE antibody, and is due to the presence of the previously described antigen-specific T cell factor (PCl-factor), that can activate serotonin-containing cells, such as mast cells, to release the vasoactive amine serotonin. PCl-factor transfers the ability to elicit an immediate hypersensitivity-like reaction that is an early component of delayed-type hypersensitivity. The presence of this T cell factor in the serum of actively sensitized mice provides a means to sensitize tissues throughout the body for this required, initial, serotonin-dependent component of delayed-type hypersensitivity reactions.
Alkylation↗
Generation, propagation, and variation in cloned, antigen-specific, Ia-restricted cytolytic T-cell lines.
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Animals↗
The specific direct interaction of helper T cells and antigen-presenting B cells.
Cell couples have been formed by mixing an antigen- and Ia-specific cloned helper T-cell line with a B-cell hybridoma presenting the antigen. By immunofluorescence observations, we have shown that the microtubule-organizing center (MTOC) inside the helper T cell, but not in the bound antigen-presenting cell, becomes oriented to face the area of specific cell-cell contact. This MTOC orientation is antigen- and Ia-specific, and thus provides direct evidence for the specific interaction of a helper T cell with a B cell. It is presumed that the function served by this MTOC orientation, which is accompanied by the coordinate reorientation of the Golgi apparatus, is to target Golgi apparatus-derived secretory vesicles, containing putative lymphokines and/or growth factors, from the helper T cell directly to the antigen-presenting cell.
Animals↗
Autocrine growth inhibition of a cloned line of helper T cells.
The growth of T lymphocytes is dependent on the T-cell growth factor interleukin 2 (IL-2), which causes T cells bearing high-affinity receptors for IL-2 to proliferate. Most cloned helper-T-cell lines can be shown to both produce and respond to IL-2; thus, growth of such cells is by an autocrine mechanism. We report that the failure of the cloned murine T-cell line D10.G4.1 to respond to its own IL-2 results from the secretion, by the same cells, of a potent inhibitor of the IL-2-driven T-cell proliferative response. This inhibition can be overcome by increasing the number of IL-2 receptors expressed by the target cell. In the cloned T-cell line producing the inhibitory substance, this increase in IL-2 receptors is driven by the monokine interleukin-1. We propose that this inhibitor of IL-2 responses may play a role in preventing "bystander" activation of T cells by IL-2 released in vivo and could be a potent pharmacologic agent.
Animals↗
Different phenotypic variants of the mouse B cell tumor A20/2J are selected by antigen- and mitogen-triggered cytotoxicity of L3T4-positive, I-A-restricted T cell clones.
The L3T4+, Lyt-2-, cloned BALB/c T cell lines 5.9.24 and 5.8.6 are cytotoxic for the BALB/c B cell tumor line A20/2J. The T cell cytotoxicity against A20/2J cells could be triggered either by the specific antigen ovalbumin (OVA), which is recognized by the T cell clones in association with I-Ad determinants, or by the T cell mitogens Con A and rabbit anti-mouse brain (RaMBr) antiserum. Repeated exposure of A20/2J cells to 5.9.24 and 5.8.6 T cell cytotoxicity selected variant cell lines that had developed resistance to cytotoxicity. The variant lines could be classified into four different variant phenotypes of which three were stably maintained in vitro. The type of variant obtained appeared to be related to the nature of the ligand used to trigger T cell cytotoxicity during selection. Cytotoxicity triggered by the antigen OVA generated type 1 variants that expressed abnormally low levels of I-Ad determinants at the cell surface. Type 1 variants were resistant to OVA-triggered 5.9.24 T cell cytotoxicity, but were fully susceptible to cytotoxicity triggered by Con A or RaMBr antiserum. RaMBr-triggered cytotoxicity generated two unique types of variant cell lines: type 3 variants that were deficient in cell surface Fc receptors and resistant to 5.9.24 cytotoxicity only when triggered by RaMBr antiserum, and type 4 variants that were resistant to cytotoxicity triggered by all three ligands. One type 4 variant, the IC-1 cell line, appeared to be resistant to soluble cytotoxic factors released by 5.9.24 T cells after activation by antigen. All of these variant lines retained sensitivity to cytotoxicity by classic Lyt-2+ cytotoxic T lymphocytes (CTL), a finding that indicates that L3T4a+ T cells and Lyt-2+ CTL use different molecules to attack their target cells. The variant phenotypes were inherited by clones derived from the original cell lines. Because the variants were generated without mutagenesis, they are thought to have been derived by the immunoselection of pre-existing variant cells that arose spontaneously in the parental A20/2J cell line. It is postulated that inheritable variation of A20/2J cells may represent changes that normally occur during B cell differentiation in response to T cell signals. The variant A20/2J cell lines described here provide material for the investigation of B cell surface structures that may regulate T-B cell interactions.
Animals↗
The immunobiology of T cell responses to Mls-locus-disparate stimulator cells. III. Helper and cytolytic functions of cloned, Mls-reactive T cell lines.
Mls-specific T cell clones derived by limiting dilution were tested for cytotoxic activity in a lectin-dependent 51Cr-release assay. All the T cell clones tested were cytotoxic in such an assay in apparent contrast to previous reports. However, only those target cells sensitive to cytolysis by other L3T4a+ cytolytic T cells were killed by Mls-specific T cell clones in short term 51Cr-release assays, possibly explaining this discrepancy. All the T cell clones tested were L3T4a+, Lyt-2- and stimulated B cells from Mlsa,d strains of mice to proliferate and secrete immunoglobulin. Furthermore, lysis of innocent bystander targets was observed when the T cells were stimulated with Mls-disparate stimulator cells. These results are consistent with those obtained with L3T4a+ T cells specific for protein antigen:self Ia and that express cytotoxic potential.
Animals↗
Cell interactions in the immune system: the role of self recognition in the targeting of nonspecific effector molecules by helper T cells.
Helper T cells are activated by cross-linking of their receptors by antigen:Ia complexes on the surface of antigen-presenting cells and B cells. As a result of this cross-linking, the helper T cell releases several lymphokines that in turn affect the Ia-bearing cell with which the helper T cell is in contact. This interaction is cognate when the effect on the target cell is examined, but it operates by a mechanism that is neither antigen specific nor MHC restricted. Whether the cognate nature of this interaction reflects solely the intimate contact of the T cell with the Ia antigen-bearing cell or whether it reflects a receptor-directed focal release of lymphokines remains to be determined. The molecular basis for functional diversity in helper T cells will have to be determined by examining the factors that regulate lymphokine gene expression in such cells, a process that appears to act at several levels.
Animals↗
Varieties of idiotype-specific helper T cells--a commentary.
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Animals↗
The role of L3T4 in T cell activation: L3T4 may be both an Ia-binding protein and a receptor that transduces a negative signal.
The T cell surface molecules Lyt-2 and L3T4 are strongly correlated with the class of MHC gene product recognized by the T cell bearing them. The L3T4 molecule has been proposed to play a role in enhancing recognition of antigen:Ia by specific T cells. In the present experiments, we have explored the role of L3T4 in T cell activation by examining the effects of the L3T4-specific monoclonal antibody GK1.5 on T cell responses in the presence or absence of class II-MHC gene products. Our studies show that GK1.5 inhibits T cell activation in the absence of class II-MHC gene products, while antibodies to other T cell surface molecules do not transduce negative signals to the same cells. We interpret our results as suggesting a signaling role for L3T4 and, by inference, for Lyt-2 as well. We would propose that L3T4 molecules on the class II-restricted T cell initiate the interaction between the L3T4+ T cell and its class II-MHC gene product bearing target cell (B cell, APC). This initial contact is important in allowing a finite time for antigen, Ia, and the T cell receptor to form an activating complex, which in turn transduces a dominant on signal to the cell. In the absence of specific antigen, or if the class II-bearing cell is of the wrong MHC genotype, so that the antigen:Ia receptor is not aggregated, then the association of L3T4 with class II molecules transduces a net negative signal to the T cell. We suggest that this negative signal is responsible for T cell:target cell deconjugation under these circumstances. Thus, we would propose that L3T4 initiates T cell:Ia-bearing cell interactions and, a finite time later, signals the T cell to discontinue the interaction unless a stimulating level of the antigen:Ia complexes for which the T cell's receptor is specific is present.
Animals↗
Molecular characterization of antibodies bearing Id-460. II. Molecular basis for Id-460 expression.
Id-460+ immunoglobulins can be induced in vivo by immunization with dinitrophenyl (DNP) or P. pneumotropica and form two nonoverlapping groups of antibodies with respect to antigen binding specificity. In this study, using Id-460+ antibodies of differing antigen binding specificities, we compared on the molecular genetic level the five gene segment combinations (VH, DH, JH, VL, and JL) that encode the variable regions of these idiotype-positive immunoglobulins. The Id-460 determinant appears to be a conformational or combinatorial determinant encoded by VH460 and VK1 crosshybridizing genes. DH, JH, and JK gene segments appear to have no measurable effect upon expression of Id-460. Finally, antigen binding specificity does not appear to simply localize to any particular gene segment but may in part be the result of somatic mutation and/or VDJH junctional sequences, whose length correlates roughly with antigen binding specificity.
Amino Acid Sequence↗
The immunobiology of the T cell response to Mls-locus-disparate stimulator cells. I. Unidirectionality, new strain combinations, and the role of Ia antigens.
The primary mixed lymphocyte reaction of T cells to Mls-locus-disparate stimulator cells differs from that to non-self Ia antigens in several respects. In the present experiments, the unidirectional nature of this response is shown in several strain combinations, including the newly detected Mlsa and Mlsa-like alleles expressed by strains PL/J, RF/J, and SM/J. All of these strains stimulate MHC-identical T cells strongly. In addition, they stimulate a variety of cloned T cell lines specific for Mlsa,d, which can thus be shown to respond to Mlsa,d stimulators of the H-2b,d,k,u, and v haplotypes. Although these results suggest that primary T cell responses to Mlsa,d are unlikely to be MHC restricted, these primary responses are readily inhibited by monoclonal antibodies specific for the I-A and especially the I-E products borne by the stimulator cells, as well as by monoclonal antibodies specific for L3T4a on the responding T cells. This effect of anti-Ia antibodies is not overcome by exogenous interleukin 1. Thus, I-A and especially I-E molecules are centrally involved in the unidirectional primary T cell response to the potently stimulating Mlsa and Mlsd alleles expressed by cells of several different MHC haplotypes.
Animals↗
The immunobiology of T cell responses to Mls-locus-disparate stimulator cells. II. Effects of Mls-locus-disparate stimulator cells on cloned, protein antigen-specific, Ia-restricted T cell lines.
Cloned, protein antigen-specific, Ia-restricted T cell lines frequently (approximately 20%) also respond strongly to stimulator cells from strains expressing stimulatory alleles at the chromosome 1-encoded Mls-locus. Furthermore, such responses are blocked by monoclonal antibodies specific for Ia antigens expressed by the stimulator rather than the responder cells. However, such responses show no specificity for polymorphic determinants on Ia molecules, although in such responses, as in primary and secondary T cell responses to stimulating Mls-locus alleles, I-E molecules appear to play a central role. These results, combined with the unique immunobiology of the primary T cell proliferative response to Mls-locus-disparate stimulator cells, suggest to us that this response involves the interaction of the receptor on T cells for antigen:self Ia with a relatively nonpolymorphic region of Ia glycoproteins. This hypothesis is supported by the observation that a monoclonal antibody to the T cell receptor will inhibit both responses, although the response to Mls-locus-disparate stimulators appears to be more sensitive to these antibodies. We propose that the interaction of the T cell receptor with Ia is stabilized by a cell interaction molecule encoded or regulated by the Mls-locus gene product permitting the T cell receptor:Ia glycoprotein interaction to lead to T cell activation.
Animals↗
Modes of cell:cell communication in the immune system.
Different cell types in the immune system appear to mediate their effects by markedly different means. B lymphocytes couple information for specificity with information for function in a single long-range molecule, antibody. Major histocompatibility complex (MHC)-restricted T cells, which we have analyzed in detail, appear to recognize antigen only on the surface of cells bearing the appropriate MHC gene product. This interaction provokes the T cell to release short-range, non-antigen-specific mediators (lymphokines) that preferentially act on the target cell bearing the antigen and stimulating the T cell. Regulatory T cells appear to make antigen-specific long-range molecules that, like antibody, combine specificity with information for function. However, unlike antibody molecules, these regulatory T cell products display recognition for particular target cells in the form of genetic restrictions. These behaviors are compared to strategies of cell:cell communication in the nervous system.
Animals↗
The role of immunoglobulin and B cells in T cell ontogeny and repertoire formation--a commentary.
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Animals↗
The Fab fragment of a directly activating monoclonal antibody that precipitates a disulfide-linked heterodimer from a helper T cell clone blocks activation by either allogeneic Ia or antigen and self-Ia.
We characterize a monoclonal antibody directed against the antigen/Ia receptor of a cloned helper T cell line that induced T cell clone proliferation and T cell clone-dependent B cell proliferation at antibody concentrations as low as 10(-11) M. A Fab fragment of this antibody was not stimulatory, implicating cross-linking of antigen receptors as the primary signal for T cell activation. The Fab fragment inhibited activation of this clone by both allogeneic Ia and antigen plus self-Ia, but not by the nonspecific stimulators concanavalin A and rabbit anti-mouse brain serum. This strongly supports the hypothesis that a single molecule mediates both self-Ia plus antigen and non-self-Ia recognition. This molecule is presumably the disulfide-linked heterodimer comprised of 42,000 mol wt acidic and basic subunits precipitated by this monoclonal antibody. The cell surface and internal precursor forms of this protein are also identified. In addition, the response to allogeneic Ia stimulation was more readily inhibited by the Fab fragment than was the response to antigen plus self-Ia, suggesting that alloreactivity reflects a low affinity interaction with a ligand represented at high frequency on the stimulatory cell.
Animals↗
Non-dinitrophenyl-binding immunoglobulin that bears a dominant idiotype (Id460) associated with antidinitrophenyl antibody is specific for an antigen on Pasteurella pneumotropica.
We have previously described an idiotype (Id460) that transiently dominates anti-2,4-dinitrophenyl (DNP) antibody responses of mice that possess the appropriate Igh-V and V kappa genotypes. Normal serum has significant levels of Id460 that does not bind DNP, and hybridomas derived from spleen cell fusions that produce monoclonal antibodies with these characteristics have been generated. Many of these monoclonal, Id460-positive antibodies bind the opportunistic mouse pathogen Pasteurella pneumotropica. P. pneumotropica induces a marked increase in serum Id460 titers without significantly increasing serum anti-DNP titers. Both normal serum and P. pneumotropica-induced Ig460-positive immunoglobulin specifically bind to P. pneumotropica. These results suggest that the normal serum Id460-positive immunoglobulin is induced by environmentally encountered antigens on P. pneumotropica. We propose that this naturally occurring Id460 activates antiidiotypic regulatory cells that in turn promote production of Id460-positive anti-DNP antibody following DNP-ovalbumin immunization. These data are compatible with those obtained in several other idiotypic systems that suggest that dominant idiotypes may be associated with antibodies that have been evolutionarily selected for expression because of their specificity for antigens on environmentally encountered pathogens.
2,4-Dinitrophenol↗