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The phorbol ester TPA is a potent protein kinase C (PKC) activator and a cofactor in the activation of the human Jurkat leukemic T cell line. We have studied the implication of the PKC signaling pathway in the process of T cell activation by generating TPA resistant mutants of Jurkat. These mutants were obtained by recovery of cells that survived a growth arrest induced by TPA. Several cellular phenomena dependent on TPA were dramatically altered in the mutated cells. The mutants were unable to form homoaggregates upon TPA stimulation. Moreover, they did not produce interleukin-2 after activation through engagement of the T cell receptor, in the presence of TPA. These results suggest that the PKC signaling pathway activated by TPA is defective in these cells. In an attempt to define and locate the defect present in the mutants, we have analysed the biochemical properties of PKC, the cellular receptor of TPA. The increase in kinase activity and the translocation of the enzyme to the plasma membrane after stimulation by TPA appeared to be normal in the mutants. We hypothesize that a metabolic step, critical for the completion of T cell activation, distinct from protein kinase C, is impaired in the mutant cells.
Mol Immunol 1991 Sep
PMID:Isolation and characterization of a T lymphocyte mutant defective in the protein kinase C signal transduction pathway. 192 9

In this review a number of uses of human T cell clones have been discussed. Before considering T cell cloning, however, it is worth bearing in mind that there are certain disadvantages to this approach to T cell immunity, not the least of which is that these cells, adapted as they are for in vitro growth, may be unrepresentative of the normal T cell, in terms of both specificity, and function. In addition, cloning is sufficiently difficult for it to be undertaken only where monoclonal populations are essential to the desired aim. Nevertheless, the range of uses discussed, and the fact that many have had a fundamental impact on our understanding of immune mechanisms, not only as mediated by T cells, but also of the intracellular mechanisms of antigen-presentation, the nature and mode of action of the cytokines, as well as the cell surface molecules and cascade of signals that orchestrate T cell activation, indicate the importance of T cell cloning. In the future, it is probable that the use of T cell clones with defined receptor usage will improve our understanding of the mechanisms underlying disease pathogenesis, and thus aid both the prevention and treatment of disease. In addition, the T cell receptor structure will, no doubt, be elucidated, leading to a further quantum leap in our understanding of T cell immune mechanisms, as well as suggesting other avenues for exploration. In all these areas there is no doubt that the methodology of T cell cloning will continue to make a fundamental contribution.
Mol Cell Probes 1990 Dec
PMID:The generation and use of human T cell clones. 208 32

Transgenic mice represent a versatile experimental approach for understanding the pathways by which the immune system regulates responsiveness to self-antigens, thereby establishing self-tolerance. The introduction of immunoglobulin and T cell receptor genes with specificity for self-antigens into the germline of mice has enabled the fate of self-reactive lymphocyte precursors to be followed in vivo. The influence of both developmentally regulated, and tissue-specific gene expression on tolerance to self-antigens has been addressed using transgenic mice expressing novel self-antigens under the transcriptional control of heterologous gene promoters. The generation of transgenic mice expressing structurally altered forms of self-antigens has allowed the role of antigen-processing in the induction of tolerance to be examined. Significantly, while these studies have confirmed the classically derived principles of immunological self-tolerance, they also point to the existence of pathways, as yet undefined, by which tolerance to self-antigens may be implemented and maintained.
Mol Biol Med 1990 Aug
PMID:Tolerance to self-antigens in transgenic mice. 223 46

Class II MHC (Ia) molecules have been shown to be critical as restriction elements in the T helper/inducer cell recognition of antigen. Efforts to determine the role of allelic variation in MHC restricted antigen presentation have included the use of serologically selected mutants to correlate structural variations in Class II molecules with changes in the antigen presenting function of Ia bearing cells. Such studies have revealed that serologically selected mutations tend to occur in a single immunodominant region and that even a single amino acid substitution can alter T cell recognition of Ia molecules. We report here the characterization of two more serologically selected Class II A beta chain mutations. Each is due to a single base change which alters a single amino acid. One of these mutations is in the third hypervariable region (amino acid 64--glutamine to arginine) and alters the antigen presenting function. The second mutation at amino acid 48, though a relatively non-conservative change (arginine to cysteine), has no effect on APC phenotype. Such a result would be predicted based on comparisons made with the proposed three dimensional crystallographic structure of Class I molecules and models proposed for Class II molecules based on Class I structure. The amino acid change at position 48 is in a portion of the molecule that is most likely unavailable to bind antigen or interact with T cell receptor whereas the mutation at amino acid 64 is on an exposed face of the alpha helix, a region which could affect interaction with either antigen and/or the T cell receptor.
Mol Immunol 1990 Jul
PMID:Functional and molecular characterization of I-A kappa beta mutants is consistent with the predicted three dimensional structure of class II MHC molecules. 239 36

The large granular lymphocyte (LGL) population, which effects a natural killer (NK) function, consists of cells whose lineage derivation has not been clearly established on the basis of phenotypic and functional properties. To clarify the relationship of LGL/NK cells to T cells we studied patterns of rearrangement and expression of the T cell receptor (Ti) genes alpha, beta, and gamma in normal human LGLs; in CD8+, CD8-, Mol+, and Mol- LGL subsets; and in 17 cases of leukemic LGL proliferations (T gamma LPD). T alpha, T beta, and T gamma genes were not expressed, nor were T beta and T gamma genes rearranged in normal LGLs or LGL subsets. The T gamma LPD were divided into two groups. One group (15/17 cases) was characterized as CD3+ and displayed Ti gene rearrangements. Seven of these cases were reactive with monoclonal antibody WT31, which suggested expression of an alpha/beta heterodimer on the cell surface. The other group (2/17 cases) was CD3- with unrearranged Ti genes. These results indicate that the normal LGL/NK population is homogeneous and distinct from the normal T cell population because it does not express, and as a result, cannot effect its immune function through the T cell receptor molecules. Conversely, T gamma LPDs represent a heterogeneous group of lymphoproliferative diseases within which the CD3-, Ti- cases most likely represent the neoplastic counterpart of normal LGL cells. The more frequent CD3+ cases may be related to recently described NK-like T cells. The observations that normal LGLs maintain germline T gamma genes and that many CD3+ T gamma LPD display an alpha/beta heterodimer suggest that a T gamma-containing receptor may not be necessary for NK or NK-like cytotoxicity.
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PMID:T cell receptor (alpha, beta, gamma) gene rearrangements and expression in normal and leukemic large granular lymphocytes/natural killer cells. 244 90

A series of T cell clones was developed from (B10 x B10.BR)F1 mice immunized with the isolated A chain of pig insulin. The T cell clones show considerable diversity as defined by their distinct reactivities to pig, beef, sheep and horse insulins in combination with the same syngeneic Ab alpha Ak beta molecules. These species variants of insulin differ from each other only in amino acid residues in position A8, A9 or A10 within the so-called A chain loop and responsiveness of mice to these variants is under Ir gene control. A detailed analysis of the stimulatory capacity of various insulin/Ia combinations including inhibition experiments with anti-Ia- and -L3T4 antibodies led to the following interpretation: the amino acid residues A8-A10 are involved in the interaction of the insulin A chain with the Ia molecules. This region can, therefore, be regarded as part of the agretope. Structural variations within this region can modify the stimulatory potency of the insulin variants. However, whether a particular amino acid substitution results in an enhancement or a reduction of the response depends on the fine specificity of the T cell clone involved. Thus, an interaction of Ia molecules with antigen cannot solely account for the functional specificity of an agretope, rather this also depends on the structure of the particular T cell receptor that participates in recognition.
Mol Immunol 1988 Jul
PMID:The specificity of the interaction between the agretope of an antigen and an Ia-molecule can depend on the T cell clonotype. 245 27

We have developed two distinct solid-phase immunoassays for the detection of antigen binding activity by products of antigen binding T cell hybridomas in the absence of MHC. Two suppressor T cell hybridomas studied (34s-18 and 34s-704) are specific for keyhole limpet hemocyanin, a protein antigen, and the other suppressor T cell hybridoma (51H7D) binds specifically to the arsonate hapten. We have adapted these hybridomas to growth in serum-free medium and have isolated molecules with antigen binding activity both from the cell membranes and from the culture fluid in which the cells had been grown. The antigen binding molecules (ABM) produced by the KLH-specific hybridomas bound best to native hemocyanin; binding was decreased when KLH was denatured by reduction and alkylation and no binding was found to an arthropod (Limulus) hemocyanin. The arsonate binding hybridoma, on the other hand, produced molecules specific for this hapten; they showed no capacity to bind KLH. The antigen binding molecules affinity-purified from all three T hybridomas have intact masses of either 145,000, 67,000 or 48,000 when run in SDS-PAGE under non-reducing conditions. Following reduction, ABM resolve in SDS-PAGE into a complex of polypeptide chains having apparent masses of 65,000, 56,000 and 49,000, with either a pair of bands at 26,000 and 22,000, or with a single band at 32,000, which is consistent with the size of translation products of mRNA previously isolated from these hybridomas. Two of the hybridomas, 34s-18 and 34s-704, used for isolation of antigen binding products in this study, were previously reported to lack detectable rearranged gamma or beta genes and therefore to lack expression of the alpha/beta or gamma/delta heterodimers. The antigen binding molecules react in solid-phase immunoassay with some antibodies specific for variable (first framework) region and joining (J) region peptide sequences predicted from T cell receptor gene sequence. Furthermore, the affinity-purified antigen binding molecules from mouse T cell hybridomas cross-react in ELISA with goat anti-rabbit IgG and not with protein G, thus allowing the use of these commercially available reagents in standard laboratory assays. Interestingly, ABM anchored in intact cell membranes, which could be shown to specifically bind antigen, did not cross-react with goat anti-rabbit IgG, indicating that the cross-reactive moiety is not detectable when the ABM are in this situation.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Immunol 1989 Jul
PMID:Solid-phase antigen binding by purified immunoproteins from antigen-specific monoclonal T cell hybridomas. 247 70

The monoclonal murine T cell hybridoma, 51H7D, was previously shown to bind the arsazobenzene hapten and to produce a soluble antigen-binding molecule. In this paper we characterize this antigen-binding immunoprotein for its relationship to known T cell receptors serologically, using antibodies specific for variable region framework, or joining region peptides predicted from gene sequence and by biochemical means. The 51H7D cell expresses a protein with subunit size of approximately 31,000, that reacts antigenically with affinity-purified antibodies directed against synthetic first framework and joining segment peptides, corresponding to the gene sequence of the T cell receptor beta chain, YT35. This molecule does not react with affinity-purified antibodies directed against murine immunoglobulin, framework 1 sequences of alpha and gamma T cell receptors, or with antibodies against synthetic heavy chain joining segments. The subunit of mol. wt. 31,000 can form higher aggregates, notably in the mol. wt range of 60,000-70,000, depending upon extraction conditions. The soluble form of the antigen-binding molecule bears the J beta cross-reactive determinant and occurs predominantly as a charge restricted molecular species of approximate mol. wt 60,000-70,000. The purified molecule has a blocked N-terminus, but quantitative statistical analysis of its amino acid composition indicates a closer relatedness to T cell receptor beta chains and other antigen-binding T cell products, than it has to alpha, gamma or delta TCR chains. No evidence for more than one type of polypeptide chain was found and the polymerization is not dependent upon the formation of disulfide bonds. These studies raise the possibility that antigen-binding soluble T cell molecules might belong to a new family of immunoproteins, that is related to, but distinct from, classical immunoglobulins and alpha beta or gamma delta heterodimers.
Mol Immunol 1989 May
PMID:A monoclonal antigen-binding T cell immunoprotein: antigenic relatedness to T cell receptor beta chain FR1 V and J peptide segments: physicochemical distinctiveness from classical immunoglobulins and T cell receptor heterodimers. 252 61

The generation of an appropriate, specific immune response to an antigen is a remarkable biological phenomenon. An examination of both allelic exclusion and lymphocyte development is critical for an understanding of this response. Over the last several years, studies using transgenic mice that carry immunoglobulin or T cell receptor transgenes have provided a more detailed understanding of the mechanism of allelic exclusion. Recently, these mice have been used to examine lymphocyte development. In the future, these mice may be used to study the role of lymphocytes in autoimmune diseases.
Mol Biol Med 1989 Aug
PMID:Allelic exclusion and lymphocyte development. Lessons from transgenic mice. 256 Jan 18

The application of DNA probes to demonstrate clonal rearrangements of the immunoglobulin heavy and light chain and T cell receptor beta chain gene loci by Southern blot hybridization analysis has led to significant advances in our ability to diagnose, classify and investigate the lymphoproliferative disorders. This approach has allowed us to conclusively determine the B or T cell lineage derivation and the clonal nature of the vast majority of lymphoid neoplasms, resulting in a new level of understanding of the biology of lymphoid neoplasia. Further application of these DNA probes to other poorly defined and controversial lymphoproliferative disorders should clarify their nature as well. Eventually, antigen receptor gene rearrangement analysis may become routinely employed in diagnosing lymphoid malignancies, monitoring the effects of chemotherapy, detecting early subclinical relapses and identifying disease progression, especially with respect to detecting the emergence of new clonal populations.
Mol Cell Probes 1987 Mar
PMID:Immunoglobulin and T cell receptor beta chain gene DNA probes in the diagnosis and classification of human lymphoid neoplasia. 284 May 74


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