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Query: UNIPROT:P06889 (Mol)
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This paper presents a dual-recognition model of the T-cell receptor that has been constructed to account for the phenomenon of MHC restriction as well as the paradoxical ability of T-cells to be both multispecific and precisely specific at the same time. In our model the combining sites for antigen and MHC are not independent as in classical dual-recognition models, but interact with each other by an allosteric mechanism. We envision a flexible receptor with combining sites for antigen and MHC that are capable of existing in a multitude of distinct complementarity states. MHC and antigen molecules act as allosteric effectors such that one ligand perturbs the conformation and therefore the specificity of the site for the other ligand. An essential feature of the model is that different MHC determinants induce different conformations at the anti-antigen site. In this way the receptor acquires multiple specificities. Within a particular complementarity state, precise recognition results from the requirement that antigen and MHC exhibit positive cooperativity in their binding to the T-cell receptor. Positive cooperativity is also the basis for MHC restriction. Reaction mechanisms are presented which describe the requirement that antigen and MHC both induce conformational changes in order to generate high-affinity binding to either ligand. As a precedent for the multistate allosteric receptor model, we discuss the properties of allosteric enzymes, especially ribonucleotide reductase, whose properties are analogous to those we have postulated for the T-cell receptor. Also discussed is the possibility that molecules such as Ly2, L3T4 and the Mls antigen, which have been found to play a role in antigen recognition, function as affinity-enhancing allosteric effectors that interact with the constant portion of the T-cell receptor.
Mol Immunol 1984 Nov
PMID:Hypothesis: the MHC-restricted T-cell receptor as a structure with two multistate allosteric combining sites. 608 44

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)
J Mol Cell Immunol 1983
PMID:The Ia molecule of the antigen-presenting cell plays a critical role in immune response gene regulation of T cell activation. 610 Oct 61

The ferredoxin (Fd) molecule is a small non-mammalian immunogenic protein containing 55 amino acid residues with only two major antigenic determinants located with the NH2-terminal heptapeptide and the COOH-terminal pentapeptide. Selective enzyme cleavages of Fd with either trypsin or carboxypeptidase A result in the inactivation of the antigenic determinants by the removal of a tripeptide at the NH2-terminal and two amino acid residues at the COOH-terminal, effectively leaving 52 and 53 amino acid fragments respectively, each containing a single antigenic determinant. Fd digested with both enzymes yielded a 50 amino acid peptide with both determinants inactivated. Purity of these digests was assessed using monoclonal antibodies in standard and antigen-blocking ELISAs. The doubly digested peptide had virtually no reactivity with anti-Fd sera, reconfirming that the central cysteine-rich region is serologically silent. It was found that the sum of the reactivities of the N- and C-determinant-bearing peptides as equal to that of the native Fd and that the ratio of the reactivities could be used to assess determinant selectivity in the response to Fd in congenic recombinant strains of mice. This method was used in mapping the determinant selectivity in the antibody response to the MHC of mice to the left of the I-B subregion. Use of the B10.HTT strain indicated that separate genes mapping to the same subregion code for the magnitude of the antibody response and the determinant selectivity of the response.
Mol Immunol 1982 May
PMID:The use of unideterminant fragments of ferredoxin in the genetic mapping of determinant specificity of the immune response. 618 Mar 12

Two monoclonal antibodies, L12/36 and L13/112, prepared from spleens of BALB/c mice immunized with extracts of the rabbit lymphoid cell line RL-5, precipitate a 42,000 mol. wt molecule from detergent lysates of this cell line. This molecule is not associated with beta-2-microglobulin (beta 2m) and has been shown by sequential precipitation experiments to be antigenically distinct from the population of class I rabbit MHC (RLA) molecules that is associated with beta 2m. In spite of this antigenic difference, amino acid sequence analyses indicate that the RLA heavy chain precipitated with anti-beta 2m and that precipitated with the monoclonal antibodies, have identical N-terminal sequences. The sequence determined to position 36 is GSHSMRYFYTSVSRPGLGXPRFIIVGYVXXTXFVRF. The isoleucine assigned to position 24 is the first species-specific residue found for RLA class I molecules. Analysis of the beta 2m associated and non-associated molecules by two-dimensional gel electrophoresis revealed no differences between the RLA heavy chains. Differences in the subcellular locations of the determinants were indicated by fluorescence microscopy and confirmed by immunoelectron microscopy. It was shown that the specificity recognized by the monoclonal antibodies is principally located on the cytoplasmic face of the plasma membrane whereas the majority of anti-beta 2m reactive specificities are on the extracellular side of the cell membrane.
Mol Immunol 1982 Nov
PMID:Rabbit MHC antigens: occurrence of non-beta-2-microglobulin-associated class I molecules. 619 Nov 99

The question of how many helper T cells are required for producing optimal antibody responses and what function each of the candidate helper cells performs are subjects of intense interest (and controversy) to the majority of immunologists. Our manuscript directly demonstrates for the first time that B cell clone growth and secretory differentiation are controlled by two distinct classes of helper T cells which can be discriminated from one another by profiles of their expressed cell surface alloantigens. There is a significant amount of inferential evidence that two types of helper T cells are required to interact with B cells and antigen in order to induce maximal antibody responses. In all reports, classical MHC-restricted, carrier-specific helper T cells (TH 1) had to interact with hapten-specific B cells via carrier-hapten bridges before the second helper cell (TH 2) could act. In contrast to the TH 1 cells, TH 2 cells have been reported neither to be MHC-restricted nor to require carrier-hapten bridges in their interaction with hapten-specific B cells. That certain isotype-, allotype-, or idiotype-expressing portions of the antigen-induced antibody response are preferentially enhanced in the presence of and depleted in the absence of the appropriate TH 2 cells has led to the suggestion that such TH 2 cells interact with B cells through receptors specific for determinants expressed on B cell surface immunoglobulin molecules. That TH 2 cells recognize autologous immunoglobulin determinants is also indirectly supported by their reported absence in appropriately immunized mice which were deficient in the relevant immunoglobulin during ontogeny [e.g. all TH 2 cells in anti-mu-treated mice; T15-specific TH 2 cells in (CBA/N X BALB/c)F1 male Xid mice which lack T15+ B cells]. It has been suggested that TH 2 cells recognize not only autologous immunoglobulin determinants but also "nominal" antigen since they have been reported to be dependent on antigen priming and reexposure to the priming antigen. However, to establish firmly that a TH 2 cell expresses receptors for both antigen and Ig determinants, one must isolate that helper cell by virtue of its receptor for one of these two moieties and show that the isolated cell has receptors for the other. We have done this, as well as showing that the Ig-recognizing, carrier-immune T cell selectively enhanced B cell secretory differentiation while having no effect on clonal expansion.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1983
PMID:Enhancement of B lymphocyte secretory differentiation by a Ly 1+,2-,Qa-1+ helper T cell subset that sees both antigen and determinants on immunoglobulin. 624 50

Helper T cells have been distinguished on the basis of whether they provide carrier-specific or nonspecific helper functions. In previous experiments we determined that the predominant class of helper T cell in populations of primed lymph node cells is a nonspecific helper T cell unable to provide carrier-specific signals. Initial induction of nonspecific helper T cells in vitro requires restimulation with the immunogen. This suggested that such T cells may express antigen-specific receptors. In this case they would constitute a unique subpopulation distinct from T cells with identical antigen-specificity that are able to provide carrier-specific help. Alternatively, the requirement for antigen restimulation might reflect a role for antigen-specific T cells in the recruitment of T cells with unrelated specificity. To distinguish between these possibilities we have characterized the specificity and function of helper T cell colonies selected from primed lymph node cells. We report here isolation of autoreactive as well as antigen-specific helper T cells. All antigen-specific T cell colonies provide carrier-specific help in the presence of the homologous hapten-carrier conjugate. Only autoreactive T cells are limited to providing nonspecific helper function. Although selection of autoreactive T cells is initially dependent on antigen restimulation in vitro, activation of an established autoreactive T cell line requires restimulation with MHC-syngeneic spleen cells but does not require restimulation with either the immunogen or fetal calf serum. These results suggest that nonspecific helper T cells induced in the course of a normal immune response to randomly chosen foreign antigens are autoreactive. Such T cells may serve to enhance proliferation and maturation to immunoglobulin secretion of B cells activated by limiting numbers of carrier-specific helper T cells. The demonstration of large numbers of precursors to MHC-specific autoreactive T cells in antigen-primed populations raises important issues concerning regulation of the expansion of autoreactive T cells in vivo.
J Mol Cell Immunol 1984
PMID:Helper functions of antigen-induced specific and autoreactive T cell colonies. 624 52

These studies address the specificity of the T cells which normally function in the in vitro primary immune response. It is generally accepted that SRBC-specific, MHC-restricted T helper cells become activated both in vivo and in vitro by seeing erythrocyte antigens presented in the context of the MHC antigens of an antigen-presenting cell. At this point, the in vivo and in vitro systems differ. In vivo, the interaction between SRBC-specific B cells and the activated T helper cells is itself also MHC-restricted, whereas in vitro, the T cell-B cell interaction is not MHC-restricted, and may be factor-mediated. It is the first phase of the in vitro response, and actually the specificity of the T cells which function in the in vitro primary response that we are questioning, in these studies. The experimental approach was to deplete antigen-specific T helper cell activity by passage of T cells through irradiated mice in the presence of a high dose of antigen, and collecting thoracic duct cells one day later. Using this protocol, we have confirmed that removal of SRBC-specific T cells ablates the adoptive transfer in vivo response to SRBC. However, the same negatively selected T cell populations were just as potent as control T cells in supporting the in vitro response to SRBC. We confirmed that the T cells removed respond to SRBC in an MHC-restricted manner by removing from an F1 T cell population the cells able to respond to SRBC in association with one parental haplotype. These T cells nonetheless provided equal help for both parental B cell populations in vitro. These experiments show that the MHC-restricted antigen-specific T cell which is required for the in vivo response is not required in the primary in vitro response to erythrocytes. The significance of this is twofold. Firstly, this demonstrates clearly that different T cells are functioning in vitro vs. in vivo. Singer and his colleagues have shown that different B cell subpopulations (Lyb5+ vs. Lyb5-), with differing MHC-restriction requirements, are preferentially activated in vivo and in vitro. Our data says that another difference between the in vivo and in vitro SRBC response is that different T cells are working in the two systems. Understanding exactly which B cell and T cell subpopulations are working within the model system (in vivo or in vitro) that an investigator chooses is obviously of critical importance.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1984
PMID:T helper cells required for the in vitro primary antibody response to SRBC are neither SRBC-specific nor MHC-restricted. 624 59

The T lymphocyte repertoire consists of clones recognizing foreign antigens together with self histocompatibility molecules. Diversification of the receptor is believed to arise by somatic mechanisms during ontogeny. MHC gene products are essential for this process as well as for antigen recognition and expression of T cell functions. Yet, the antigen-specific T cell receptor is not encoded by MHC genes. Little is still known concerning the nature and the genetic origin of this receptor despite numerous experimental approaches. Although the T cell repertoire is mainly determined, in a single individual, by the alleles expressed at the MHC locus, one can postulate that it could also be influenced by the existence of alleles of the germ line gene(s) encoding the T cell receptor. If so, an analysis of the T cell fine specificity in mice of the same H-2 haplotype with different background genes might permit the mapping of the genes coding for this receptor. Such an experimental approach requires the use of an antigen consisting of only one major determinant. Several recent observations suggested to us that the hapten p-azobenzenearsonate (ABA) was a suitable model for such investigations. Thus, we decided to compare the specific pattern of responses to ABA-tyrosine, ABA-histidine and to free ABA in different inbred mouse strains. We report here that the lymph node T cell proliferative response to these molecules is under the control of an ABA-specific Ir gene. The ABA-Tyr conjugate is the most potent immunogen of the three in vivo as well as in vitro. High responder strains to ABA-His or ABA are included in the group of high responders to ABA-Tyr suggesting that the response to the three molecules is under the control of the same Ir-gene. The pattern of the response is also influenced by background gene(s). One of these can be localized on chromosome 12 using congenic mice. No close linkage to IgCH markers or VH idiotypes can be demonstrated but a linkage of this gene(s) to the Pre-1 locus seems possible. B lymphocytes do not seem to account for the involvement of Chr.12-genes in the response since; in our experimental system, they do not present ABA to T cells nor do they proliferate in the assays. Similarly, ABA-Tyr-antibody complexes do not enhance macrophages presentation of ABA to T cells, which supports the conclusion that IgCH or VH gene products are not involved in the control of the response.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1984
PMID:Interaction between genes of chromosome 12 and I-region genes in the control of the arsonate-specific T cell repertoire. 644 53

Detailed analysis of the role of the structural characteristics of these molecules will require isolation of relatively large amounts of these antigens in serologically active form. We have purified murine Ia antigens on a large scale by affinity chromatography using monoclonal antibodies coupled to Sepharose 4B. Both I-Ak and I-Ek were isolated by sequential passage of cell lysate over columns prepared using specific monoclonal antibodies. Elution of the bound antigens required high pH (11-12) but, nonetheless, the purified material was 50-75% serologically active. Using LPS-stimulated spleen cells or B-lymphocyte tumor cells as starting material, 0.5 mg of each antigen can be readily purified. Based on antigen yields, it can be estimated that normal B-cells have about the same surface density of Class I and Class II MHC antigens. LPS blasts, in contrast, have normal levels of Class I antigen but 3-5 times higher levels of Class II antigens. We have now purified I-Ak and I-Ek from a number of different cell sources and have noted differences in both the mol. wts of the alpha- and beta-chains and in their apparent associations with cytoskeletal components. Proteins having the same apparent mol. wts as actin and myosin co-purify with both I-Ak and I-Ek antigens from various sources. These proteins do not co-purify with H-2K and D molecules obtained by similar methods, suggesting that Ia antigens may specifically interact with cytoskeletal elements.
Mol Immunol 1983 Nov
PMID:Large-scale purification of murine I-Ak and I-Ek antigens and characterization of the purified proteins. 658 82

The E1 serum was developed against invariant chain peptide Ii (183-193) in order to study the function of the Ii protein which associates with class II MHC alpha,beta chains from time of synthesis until cleavage and release, possibly regulating the binding of antigenic peptides. Subpopulations of Ii, Ii(VIC) and Ii(E1), respectively, were demonstrated by sequential immunodepletions and immunoprecipitations with: (1) VIC-Y1 monoclonal antibody to an N-terminal epitope of Ii, and (2) E1 rabbit antiserum to Ii(183-193). In 3 hr radiolabeled cells, VIC-Y1 recognized Ii, Ii and N- and O-linked glycosylation (IpN, IpO), p41 and co-precipitated class II alpha,beta chains, while E1 recognized Ii, IpN and immature Ii-alpha complex. In 15 min radiolabeled cells, each antibody recognized similar, immature Ii forms without alpha,beta. Urea denaturation of Ii(VIC) rendered the main Ii species but not IpO immunoprecipitable with E1. E1 recognized O-glycanase-treated Ii (VIC). We conclude that the Ii(183-193) epitope was obscured by interactions of Ii with class II alpha,beta chains and by the O-linked glycosylation of Thr187, which may in part regulate association of Ii to class II alpha and beta chains.
Mol Immunol 1993 Dec
PMID:Characterization of the invariant chain C-terminus (Glu183-Glu193) epitope which is obscured in processed Ii, MHC alpha,beta trimers. 750 83


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