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In the previous paper in this series, we described a form of self-reactivity among T cells called the "syngeneic T-T lymphocyte reaction" (STTLR). The phenomenon involves responder T cells that are stimulated to proliferate by irradiated antigen or self-reactive cloned T cell lines. The proliferative STTLR occurs in cultures rigorously depleted of conventional APC and is inhibitable by anti-Ia antibodies of the appropriate specificity. We also showed that both L3T4+ Lyt2- and L3T4- Lyt2+ T cell subsets participate in the STTLR-induced by the IEk-specific Lbd T cell line. In this paper, we report our studies on the effector phase of STTLRs, in particular, the cytotoxic responses induced by Lbd cells. We demonstrate that uncloned and cloned lines (called Dbl) of anti-Lbd cytotoxic cells are L3T4- Lyt2+ effector cells that kill Lbd, antigen-reactive T cells, and syngeneic B cells stimulated with LPS. They also kill syngeneic splenic cells stimulated with Con A for 72 h or less; longer culture periods in the presence of Con A yield Dbl-resistant T cells. Resting T cells are also resistant to Dbl cells. Using LPS-induced splenic B cells from H-2 congenic mice, we map the anti-self specificity of uncloned and cloned anti-Lbd cells to the Kk + IAk regions of the MHC. Seemingly concordant results were obtained using L transformants expressing IAk molecules on their surface. However, control studies with fibroblast lines and UV-induced fibrosarcoma cells unexpectedly revealed a high susceptibility to lysis by Dbl cells among certain Ia- cell lines. These results suggested that the antigen recognized by Dbl cells is not IAk itself but either an MHC-encoded or MHC-regulated gene product expressed by activated T and B cells and certain tumor cells. The target antigen is important in immunoregulation because Dbl cells suppress both the proliferation of Lbd cells to syngeneic cells and primary T cell-dependent anti-SRC PFC responses. From an immunoregulatory viewpoint, the existence of Lbd-Dbl cells offers several appealing features. Since Lbd cells cannot activate resting B cells or replace antigen-specific helper cells, they cannot initiate immune responses nonspecifically. In the presence of the appropriate antigen-specific helper T cells, Lbd and other self-reactive cells can amplify an immune response and thus facilitate its exponential growth. Since the self-reactive cells activate the Dbl cytotoxic circuit described above, they also provide the stimulus required to terminate immune responses quickly.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Immunol 1986
PMID:The syngeneic T-T lymphocyte reaction (STTLR). II. Induction of primary T anti-T cell cytotoxic responses in vitro in T cell cultures stimulated with syngeneic self-reactive T cells. 350 19

The amidase genes of Pseudomonas aeruginosa were inserted into a lambda replacement vector following cleavage with the restriction endonuclease HindIII. The recombinant lambdaami was detected by enhanced growth of Escherichia coli around plaques of the recombinant phage on minimal medium containing acetamide as the nitrogen source. Low levels of amidase activity were detected in E. coli cultures infected with lambdaami and these were sufficient to allow growth with acetamide as nitrogen source. Lysis-defective derivatives of lambdaami were made by introducing Q-, S-, mutations. Cultures of E. coli infected with lambdaamiQ-S- synthesised amidase as the major protein. The amidase produced by these cultures was identical to that produced by PAC strains of P. aeruginosa in substrate specificty, thermal stability and immunological cross-reaction.
Mol Gen Genet 1980 Jan
PMID:The construction in vitro of derivatives of bacteriophage lambda carrying the amidase genes of Pseudomonas aeruginosa. 624 42

The MHC class II molecules bind antigenic peptides and present them to T cells. Their ability to carry out these functions depends, in a critical way, on the detailed structure of the membrane-distal alpha 1 and beta 1 domains of these molecules. Using the I-Ak molecule and a series of hen egg lysozyme (HEL) peptide-specific, I-Ak-restricted T cell hybridomas as a model, we have examined the effect of altering essentially all of the polymorphic residues of the murine class II molecule on its ability to present Ag. Our results support the following conclusions: (1) both the location and the structural alteration introduced in a specific amino acid interchange are important in determining the effect the interchange will have on Ag presentation; and (2) changes in amino acids in the floor of the putative Ag binding cleft of the class II molecule can exert a major influence on the presentation of peptides to T cells. By carrying out direct binding experiments between the HEL(46-61) peptide and two mutant I-A molecules that fail to present HEL(46-61) to appropriate T cells, we were able to assess, in a quantitative fashion, the role played by peptide binding in the failure to present Ag. Our results suggest that, in the two cases studied, the failure to bind the HEL(46-61) peptide was not primarily responsible for the failure of the mutant class II molecule to present that peptide. Specifically, an A beta chain mutant that possesses d allelic residues at positions 65-67 in the second PMR of the Ak beta chain actually binds HEL(46-61) at wild type (I-Ak) levels. In contrast, an A alpha chain chimera in which b allelic residues are inserted in the third PMR of the Ak alpha chain, binds HEL(46-61) about three- to four-fold less well than wild type. While this decrease in binding affinity may be partially responsible for the inability of the latter chimeric molecule to present HEL(46-61), it can not be the total explanation because increasing the peptide concn even by an order of magnitude does not restore Ag presentation by APC expressing this chimeric molecule. These results are discussed in terms of the currently accepted model of the class II molecule.
Mol Immunol 1993 Apr
PMID:Functional analysis of the antigen binding region of an MHC class II molecule. 768 33

An earlier study has shown that FAP patients with mutations in codons 136-302 of the APC gene do not develop congenital hypertrophy of the retinal pigment epithelium (CHRPE), whereas those with mutations in codons 463-1387 regularly do. Here we present data on 36 patients from 20 families with mutations in codons 1445-1578. These patients lack CHRPE. Furthermore, with the exception of three prepubertal children all patients with mutations in codons 1445-1578 developed desmoid tumours. This relationship between certain extracolonic manifestations and site of the APC mutation points to a specific role of the APC protein in different tissues.
Hum Mol Genet 1995 Mar
PMID:Familial adenomatous polyposis: desmoid tumours and lack of ophthalmic lesions (CHRPE) associated with APC mutations beyond codon 1444. 779 85

Mutations or loss of the APC tumor-suppressor gene is important for the development of colorectal polyps and cancers, but little is known about the function of this gene in normal tissue. To study the role of APC and other genes in colonocytes in vivo, a system was developed whereby transient expression of genes is established in normal rodent colonic epithelium, using liposomal gene delivery by rectal catheter infusion. Expression of a beta-galactosidase reporter gene and of the human APC gene under a constitutive promoter is demonstrated. A high efficiency of transfection is maintained, with close to 100% of epithelial cells expressing the introduced gene. Expression is transient and does not persist beyond 4 days, consistent with the normal turnover time of gut epithelium, but it can be maintained by repeated treatments. Human APC was expressed for three weeks under these conditions at approximately one-tenth the level of the endogenous APC gene, and no toxicity was observed beyond that attributed to repeated rectal enemas. These results reveal that in vivo expression of exogenous gene is feasible using a liposomal delivery system and suggest a method to further study the physiologic role of APC or other genes in the interrelated process of colonic epithelial proliferation and differentiation.
Hum Mol Genet 1994 Nov
PMID:Human APC gene expression in rodent colonic epithelium in vivo using liposomal gene delivery. 787 18

beta-catenin was identified as a cytoplasmic cadherin-associated protein required for cadherin adhesive function (Nagafuchi, A., and M. Takeichi. 1989. Cell Regul. 1:37-44; Ozawa, M., H. Baribault, and R. Kemler. 1989. EMBO [Eur. Mol. Biol. Organ.] J. 8:1711-1717). Subsequently, it was found to be the vertebrate homologue of the Drosophila segment polarity gene product Armadillo (McCrea, P. D., C. W. Turck, and B. Gumbiner. 1991. Science [Wash. DC]. 254:1359-1361; Peifer, M., and E. Wieschaus. 1990. Cell. 63:1167-1178). Also, antibody perturbation experiments implicated beta-catenin in axial patterning of the early Xenopus embryo (McCrea, P. D., W. M. Brieher, and B. M. Gumbiner. 1993. J. Cell Biol. 123:477-484). Here we report that overexpression of beta-catenin in the ventral side of the early Xenopus embryo, by injection of synthetic beta-catenin mRNA, induces the formation of a complete secondary body axis. Furthermore, an analysis of beta-catenin deletion constructs demonstrates that the internal armadillo repeat region is both necessary and sufficient to induce axis duplication. This region interacts with C-cadherin and with the APC tumor suppressor protein, but not with alpha-catenin, that requires the amino-terminal region of beta-catenin to bind to the complex. Since alpha-catenin is required for cadherin-mediated adhesion, the armadillo repeat region alone probably cannot promote cell adhesion, making it unlikely that beta-catenin induces axis duplication by increasing cell adhesion. We propose, rather, that beta-catenin acts in this circumstance as an intracellular signaling molecule. Subcellular fractionation demonstrated that all of the beta-catenin constructs that contain the armadillo repeat domain were present in both the soluble cytosolic and the membrane fraction. Immunofluorescence staining confirmed the plasma membrane and cytoplasmic localization of the constructs containing the armadillo repeat region, but revealed that they also accumulate in the nucleus, especially the construct containing only the armadillo repeat domain. These findings and the beta-catenin protein interaction data offer several intriguing possibilities for the site of action or the protein targets of beta-catenin signaling activity.
 ...
PMID:Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling. 787 19

The effects of a 7-day intraperitoneal infusion with VIP (0.03 nmol.kg-1.min-1) and its antagonist [4-Cl-D-Phe6,Leu17]-VIP (VIP-A; 3 nmol.kg-1.min-1) were studied in sham and bilaterally adrenalectomized rats bearing ACTH and angiotensin II (ANG-II)-responsive adrenocortical autotransplants. VIP significantly increased plasma aldosterone (ALDO) concentration (PAC) and lowered plasma renin activity (PRA) in both groups of animals, without affecting plasma levels of ACTH and corticosterone. This treatment caused a marked hypertrophy of adrenal zona glomerulosa (ZG) and its parenchymal cells (without inducing any significant change in the zona-fasciculata morphology), as well as of ZG-like cells of autotransplants. Isolated ZG cells and autotransplant quarters obtained from VIP-infused rats evidenced a notable increase in both their basal and maximally ACTH- or ANG-II-stimulated ALDO secretion. The simultaneous infusion of rats with VIP-A completely reversed all these effects of VIP. The infusion with VIP-A alone caused, in sham-operated rats, a net decrease in PAC, coupled with a rise in PRA, and a marked atrophy of ZG and ZG cells; basal and maximally stimulated ALDO secretion of dispersed ZG cells was also significantly lowered. Conversely, VIP-A did not evoke any appreciable effect in autotransplanted rats. These findings suggest that endogenous VIP is specifically involved in the maintenance of the growth and secretory capacity of rat adrenal ZG. Since regenerated adrenocortical autotransplants, which are responsive to VIP but not to VIP-A infusion, are completely deprived of chromaffin cells, the hypothesis is advanced that adrenal medulla may be the source of endogenous VIP regulating ZG function.
J Steroid Biochem Mol Biol 1994 Oct
PMID:Evidence that endogenous vasoactive intestinal peptide (VIP) plays a role in the maintenance of the growth and steroidogenic capacity of rat adrenal zona glomerulosa. 794 54

We identified a partially sequenced Saccharomyces cerevisiae gene which encodes a protein related to the S. cerevisiae RNA polymerase II subunit, RPB7. Several lines of evidence suggest that this related gene, YKL1, encodes the RNA polymerase III subunit C25. C25, like RPB7, is present in submolar ratios, easily dissociates from the enzyme, is essential for cell growth and viability, but is not required in certain transcription assays in vitro. YKL1 has ABF-1 and PAC upstream sequences often present in RNA polymerase subunit genes. The sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility of the YKL1 gene product is equivalent to that of the RNA polymerase III subunit C25. Finally, a C25 conditional mutant grown at the nonpermissive temperature synthesizes tRNA at reduced rates relative to 5.8S rRNA, a hallmark of all characterized RNA polymerase III mutants.
Mol Cell Biol 1994 Sep
PMID:C25, an essential RNA polymerase III subunit related to the RNA polymerase II subunit RPB7. 806 49

Genetic transformation of Leishmania has relied upon two exogenous selectable markers, neo and hyg, encoding resistance to G418 and hygromycin B respectively. There is a need for multiple independent selectable markers, since Leishmania is diploid and experimental sexual crosses are not currently feasible. Here we report on the development of two additional markers: pac, conferring resistance to the glycopeptide antibiotic puromycin, and phleo, conferring resistance to the DNA-binding drug phleomycin. We constructed a set of four analogous shuttle vectors with these four markers, using DNA segments flanking the Leishmania major H region hmtxr gene to provide information required for expression. These constructs (pHM-NEO, pHM-HYG, pHM-PAC and pHM-PHLEO) were successfully transfected into L. major, mostly with efficiencies comparable to those observed with previous DHFR-TS-based neo and hyg-containing constructs. The exception was pHM-PHLEO, which transfected 30-fold less efficiently; this may be related to the nonenzymatic mechanism of resistance encoded by phleo. All four constructs were shown to replicate extra-chromosomally. Stable transfectants bearing all paired combinations of pHM constructs were obtained by a second round of transfection. These data show that the four markers are functionally independent and in conjunction with the Leishmania N-acetylglucosaminyl transferase gene, brings the number of selectable markers available in Leishmania to five.
Mol Biochem Parasitol 1993 Nov
PMID:Two more independent selectable markers for stable transfection of Leishmania. 811 24

In the course of presymptomatic diagnosis in families with familial adenomatous polyposis (FAP) we screened 202 unrelated patients for mutations in the APC gene. Germ-line mutations were identified in 20.8% of the index patients by a single step screening procedure based on heteroduplex analysis of a PCR product encompassing codons 1027-1384 of the APC gene. The most common mutations in our sample were a 5 bp deletion at codon 1309 in 9% of the families, a 5 bp deletion at codon 1061 in 5% and a 4 bp deletion at codon 1068 in 2.5% of the families. In addition, 11 novel mutations localized within the exons 11-15 of the APC gene were identified by the heteroduplex or SSCP methods.
Hum Mol Genet 1994 Jan
PMID:Frequency of common and novel inactivating APC mutations in 202 families with familial adenomatous polyposis. 816 22


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