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J H Russell

Publications and source records attributed to J H Russell.

At least 55 records · Page 3Linked to original sources
PubMed1990

Evidence for CD8-independent T cell maturation in transgenic mice.

Double-negative (CD4-/CD8-) T cells expressing the alpha/beta transgenic TCR from the 2C cell line (anti-H-2Ld) were examined in the periphery of animals whose MHC type produces positive, negative, or no selection for differentiation of the TCR on single positive (CD8+) cells. Regardless of the selection haplotype the CD4-/CD8- cells are capable of activation by anticlonotypic mAb indicating that negative selection does not inactivate the "forbidden" TCR. Rather, the lack of response to H-2Ld in the negative haplotype is likely to absence of CD8 required to produce a functional response to H-2Ld. The similarity of surface phenotype and functional activity of these CD4-/CD8- cells maturing in different haplotypes suggests they may arise by an alternative lineage which, unlike the dominant TCR alpha/beta pathway, does not require coexpression of CD4/CD8.

Animals↗
PubMed1990

Positive selection of transgenic receptor-bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding.

A specific interaction between the class I major histocompatibility complex molecule Kb and thymocytes expressing the antigen receptor from the cytolytic T lymphocyte 2C enhances maturation of T cells of the CD8 lineage in transgenic mice. By analyzing transgenic mice backcrossed to Kbm mutant strains of mice, we have identified five bm mutations of the Kb antigen-encoding gene that alter the positive selection of thymocytes induced by Kb antigen. Compared with Kb, Kbm10 and Kbm1 did not induce significant maturation of 2C T-cell receptor-bearing thymocytes, and Kbm8 antigen positively selected for transgenic thymocytes only weakly. Altering residue 77 of Kb molecule from aspartic acid to serine made Kbm3 and Kbm11 allogeneic targets for the 2C antigen receptor and caused deletion of transgenic thymocytes. This deletion spared T cells that expressed low levels of CD8, a result differing from the total deletion of CD8-bearing T cells seen in mice that expressed the original target alloantigen Ld. This evidence indicates that (i) self-peptides bound to thymic major histocompatibility complex molecules can influence the positive selection of thymocytes and (ii) thymocytes with apparently weak interaction with self-major histocompatibility complex antigens can escape clonal deletion.

Animals↗
PubMed1990

Water movement in yellow-cedar seedlings and rooted cuttings: comparison of whole plant and root system pressurization methods.

One-year-old yellow-cedar (Chamaecyparis nootkatensis (D. Don) Spach) seedlings and rooted cuttings were taken from cold-storage facilities and grown in aerated water in a controlled environment room for 21 days. Root areas of seedlings and rooted cuttings were initially comparable, but after 21 days seedlings had produced more than twice as much new root area as rooted cuttings. Water flow resistance through the plant-atmosphere continuum decreased in both stock types over the 21-day period. In both seedlings and rooted cuttings, transpirational flux density increased in a curvilinear manner as new root area increased. Root resistance to water movement decreased sharply with increasing new root area up to 20 cm(2) in both seedlings and rooted cuttings. Further increases in new root area did not result in further changes in root resistance of either stocktype. Plant water movement was measured by both the whole plant and the root system pressurization methods with results differing between the two techniques.

Journal Article↗
PubMed1989

Protein kinase C regulation of terminal deoxynucleotidyl transferase.

Terminal deoxynucleotidyl transferase (TdT) is a nuclear enzyme found in early lymphocytes which is thought to increase junctional diversity of TCR and Ig genes by the addition of N regions. TdT is normally found only in immature lymphoid cells and is turned off in both mature B and T cells. To investigate the regulation of TdT gene expression, pre-B and pre-T cells were treated with PMA or three of its analogs and its effects on steady-state TdT mRNA levels determined. Rapid and reversible decline in steady-state TdT mRNA levels was observed within 6 h with PMA. This rapid decline can be blocked by pretreatment of the cells with a relatively selective protein kinase C inhibitor implicating the role of protein kinase C activation in the decline of TdT mRNA. Nuclear run-off studies demonstrate that TdT transcription is rapidly down-regulated within 45 min after PMA treatment, indicating that this regulation occurs mainly at the level of transcription. Furthermore, the TdT mRNA decline is blocked in the presence of cycloheximide, showing that new protein synthesis is required for inactivation of the gene.

Animals↗
PubMed1989

Cytotoxic T lymphocyte-induced loss of target cell adhesion and lysis involve common and separate signaling pathways.

Recently, we demonstrated that an early event in the CTL-target cell (TC) interaction is loss of TC adherence to substrate. This loss of adhesion is Ag-specific, but distinct from the lytic event because it can ensue in nominally Ca2+-free medium. In this study, we examine further the mechanism of CTL-induced loss of adhesion, concentrating mainly on the signal transduction pathway. Based on the differential sensitivity of CTL to extracellular Ca2+, protein kinase C activation/depletion and inhibition by anti-Lyt-2 (CD8) or anti-CTL receptor (TCR) reagents, we demonstrate that CTL-induced loss of adhesion can be initiated through multiple activation pathways. Although CTL-mediated lysis is restricted to a Ca2+ and protein kinase C-dependent signaling mechanism, CTL-induced loss of adhesion is initiated in the presence or absence of extracellular Ca2+ or functional protein kinase C activity. Furthermore, although under physiologic conditions, anti-CD8 or anti-TCR reagents strongly block both CTL activities, under non-lytic conditions, they fail to inhibit the ability of CTL to promote loss of adhesion. These findings implicate the participation of additional CTL-TC ligand interactions resulting in loss of adhesion, and thus, provide further evidence to support the hypothesis that CTL-induced loss of adhesion can be initiated through multiple triggering pathways.

Animals↗
PubMed1989

Inhibition of cytotoxic T lymphocyte-mediated lysis and cellular proliferation by isoquinoline sulfonamide protein kinase inhibitors. Evidence for the involvement of protein kinase C in lymphocyte function.

The effects of the isoquinoline sulfonamides, a class of synthetic protein kinase inhibitors, namely 1-(5-isoquinoline sulfonyl)-2-methylpiperazine dihydrochloride (H7), N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride (H8), N-(2-aminoethyl)-5-isoquinoline sulfonamide dihydrochloride (H9), and N-(2-guanidinoethyl)-5-isoquinoline sulfonamide hydrochloride (HA1004), on the lytic activity of in vivo-produced (H-2b anti-H-2d alloimmune) cytotoxic T lymphocytes (CTL) were investigated. The hierarchy of inhibition of lysis shown by these compounds resembled that of their inhibition of Ca2+/phospholipid-dependent enzyme (protein kinase C). H7 has the highest affinity for protein kinase C (Hidaka, H., Inagaki, M., Kawamoto, S., and Sasaki, Y. (1984) Biochemistry 23, 5036-5041) and gave the greatest inhibition of lysis by CTL. HA1004 has the weakest affinity for protein kinase C and gave very little inhibition of lysis, whereas H8 and H9 showed intermediate inhibition of lysis. In addition, the effect of the isoquinoline sulfonamides on cellular proliferation was examined. Interestingly, the pattern of inhibition observed for both lymphocytes and tumor cells closely mimicked the effects of these compounds on protein kinase C activity. These results demonstrate that modulation of an early biochemical signal affects both short-term (e.g. CTL-mediated lysis) and long-term (e.g. cellular proliferation) events. These data provide further evidence for the integral role of protein kinase C in the activation of the lytic signal in CTL. In addition, suggestive evidence is provided that protein kinase C, or some other enzyme with similar sensitivity to the isoquinoline sulfonamides, plays an important role in cellular proliferation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1988

Positive and negative selection of an antigen receptor on T cells in transgenic mice.

The T-cell repertoire found in the periphery is thought to be shaped by two developmental events in the thymus that involve the antigen receptors of T lymphocytes. First, interactions between T cells and major histocompatibility complex (MHC) molecules select a T-cell repertoire skewed towards recognition of antigens in the context of self-MHC molecules. In addition, T cells that react strongly to self-MHC molecules are eliminated by a process called self-tolerance. We have recently described transgenic mice expressing the alpha beta T-cell receptor from the cytotoxic T lymphocyte 2C (ref. 11). The clone 2C was derived from a BALB.B (H-2b) anti-BALB/c (H-2d) mixed lymphocyte culture and is specific for the Ld class I MHC antigen. In transgenic H-2b mice, a large fraction of T cells in the periphery expressed the 2C T-cell receptor. These T cells were predominantly CD4-CD8+ and were able to specifically lyse target cells bearing Ld. We now report that in the periphery of transgenic mice expressing Ld, functional T cells bearing the 2C T-cell receptor were deleted. This elimination of autoreactive T cells appears to take place at or before the CD4+CD8+ stage in thymocyte development. In addition, we report that in H-2s mice, a non-autoreactive target haplotype, large numbers of CD8+ T cells bearing the 2C T-cell receptor were not found, providing strong evidence for the positive selection of the 2C T-cell receptor specificity by H-2b molecules.

Animals↗
PubMed1988

Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice.

The major problem in the study of T-cell development is that of tracking thymocytes of a given specificity. Recent studies have exploited natural correlations between the expression of a particular V beta gene segment and T-cell receptor (TCR) specificity. We and others (refs 5, 6 and M. Davis, personal communication) have taken an alternative approach. We have generated transgenic mice expressing the alpha beta antigen receptor from the cytotoxic T-lymphocyte clone 2C (ref. 7). In transgenic mice of the same haplotype as the 2C clone, the 2C TCR was expressed on 20-95% of peripheral T cells. Very few of these T cells carried the CD4 antigen; the vast majority were CD4-CD8+ and were able to lyse targets with the same specificity as the original 2C clone. These results indicate that the alpha beta heterodimer transfers specificity to recipient cells as expected from earlier studies, and that receptor specificity in T-cell repertoire selection is determined by both alpha beta heterodimer and CD4 or CD8 accessory molecules.

Animals↗
PubMed1988

Phosphorylation of a 15- to 17-kDa protein correlated with lytic function in cytotoxic T lymphocytes.

CTL are activated to lyse their targets through the interaction of the CTL-R and the appropriate Ag on the surface of the target cell. Experiments with tumor-promoting phorbol esters have suggested that the activation and translocation of protein kinase C (PKC) to the CTL membrane may be important in the activation process. We have studied the functional role of PKC in lytic signal transduction by correlating the phosphorylation of a set of CTL membrane proteins bound by the lectin Con A with lytic function in CTL clones. The data obtained indicate that the phosphorylation of a 15- to 17-kDa polypeptide in this subset is associated with the translocation of PKC to the membrane and the stimulation of lytic function. This suggests that the 15- to 17-kDa protein may be a physiologically relevant substrate for PKC translocated to the membrane as a result of Ag-specific perturbation of the CTL-R.

Concanavalin A↗
PubMed1988

Antigen as a positive and negative regulator of proliferation in cytotoxic lymphocytes. A model for the differential regulation of proliferation and lytic activity.

The goal of these experiments has been to capitalize on the functionally distinct responses of heteroclitic CTL to cross-reactive Ag to explore the role of Ag in regulating CTL proliferation and lytic function. The experiments here have examined one of these clones in detail but several such clones appear similar. The principal findings were: 1) proliferation and lysis may be optimally stimulated by quantitatively different interactions, 2) Ag can have negative as well as positive effects on the proliferative potential of the responding cell, and 3) both positive and negative effects on lysis can be mimicked by agents which are similar to the second messengers produced by stimulating the TCR.

Animals↗
PubMed1988

Loss of adhesion. A novel and distinct effect of the cytotoxic T lymphocyte-target interaction.

The ability of adherent target cells to remain attached to their substratum is lost as an early consequence of interaction with cytotoxic T lymphocytes. This phenomenon is shown to be a distinct event in the lytic process induced by cytotoxic T lymphocytes and does not occur during lysis by antibody plus complement. Thus loss of adhesion represents a previously unrecognized form of immune damage which may have important implications in both normal and pathologic responses.

Animals↗
PubMed1987

In vivo depletion of mannose receptor bearing cells from rat liver by ricin A chain: effects on clearance of beta-glucuronidase.

Ricin A chain has previously been shown to intoxicate macrophages in vitro following binding and endocytosis by the macrophage mannose receptor. In this report it is demonstrated that the intravenous injection of ricin A chain in nephrectomized rats leads to a prolonged plasma half-life for [125I]beta-glucuronidase, a ligand for the mannose receptor. Clearance of [125I]asialofetuin, a ligand for the galactose receptor of hepatocytes, was unaffected by injection of A chain. Microscopic examination of the livers of A chain-treated animals revealed a loss of phagocytic cells from the liver sinusoids. These results suggest that ricin A chain may be useful as a toxin specific for mannose receptor bearing cells of the reticuloendothelial system.

Animals↗
PubMed1987

The role of K+ in the regulation of the increase in intracellular Ca2+ mediated by the T lymphocyte antigen receptor.

The regulation of the increase in intracellular calcium ([Ca2+]i) occurring in cytolytic T lymphocytes (CTLs) upon their interaction with antigen was examined. This [Ca2+]i increase and lytic function were insensitive to verapamil, a Ca channel blocker. An antigen-independent increase in [Ca2+]i was not induced by depolarization of CTLs with excess extracellular K+, suggesting that Ca2+ influx is not mediated by the ubiquitous voltage-gated Ca channel. The antigen-induced [Ca2+]i increase was inhibited by prior membrane hyperpolarization with valinomycin. Hyperpolarization occurred under normal circumstances in CTLs exposed to antigen-receptor-specific antibodies. This potential change was Ca2+-dependent and inhibited by K channel blockade. Conversely, K channel blockade augmented the antigen-specific [Ca2+]i increase while markedly decreasing the K+ efflux associated with CTL lytic function. Therefore, either membrane potential or intracellular K+ regulates the antigen-specific [Ca2+]i increase in CTLs.

Animals↗
PubMed1987

MHC-specific cytotoxic T lymphocyte killing of dissociated sympathetic neuronal cultures.

Experiments were conducted to determine whether neurons in culture can serve as targets for immunologic attack mediated by major histocompatibility complex (MHC)-specific cytotoxic T lymphocytes (CTLs) which recognize Class I antigens. Allogeneic C3H/He primary neuronal cultures were quickly destroyed after CTL addition, while syngeneic C57BL/6J neurons were not lysed. Alterations in the distribution of chromatin were the first ultrastructural changes that occurred, followed by loss of nuclear morphology, cytosolic changes, and eventually fragmentation of both the nucleus and cytosol. With Campenot chambers, it was possible to separate the membrane and nuclear lesions. CTLs exposed to neurites, but separated from the cell body by the chamber barrier, caused degeneration of neurites but did not cause lysis and cell death. Neuronal lysis mediated by antibody and complement appeared to be distinct from CTL-mediated lysis. These experiments demonstrate that neurons in culture are targets for MHC-specific CTLs, and therefore probably express functional levels of Class I antigens. The signal for killing by CTLs is not retrogradely transported from the neurite to the cell body, and morphologic events following CTL-neuron interaction resemble those that occur in dividing tumor target cell populations.

Animals↗
PubMed1986

Antagonistic effects of phorbol esters on lymphocyte activation. Evidence that protein kinase C provides an early signal associated with lytic function.

There is increasing evidence that protein kinase C plays a role in the transduction of an activation signal in lymphocytes. The bulk of this evidence is based on pharmacological experiments involving the tumor promoter phorbol myristate acetate (PMA) as a protein kinase C agonist. However, in cytotoxic T lymphocytes, PMA has been shown to both stimulate and inhibit lytic function. By examining the effects of a series of phorbol esters on protein kinase C activity in lymphocytes, we will demonstrate that these antagonistic effects of PMA on cytotoxic T lymphocyte function are related to multiple effects of PMA on protein kinase C activity.

Animals↗
PubMed1986

Mannose receptor-mediated uptake of ricin toxin and ricin A chain by macrophages. Multiple intracellular pathways for a chain translocation.

The role of the high mannose carbohydrate chains in the mechanism of action of ricin toxin was investigated. Ricin is taken up by two routes in macrophages, by binding to cell surface mannose receptors, or by binding of the ricin galactose receptor to cell surface glycoproteins. Removal of carbohydrate from ricin by periodate oxidation led to a large loss in toxicity via both routes of uptake by an effect on the B chain not due to a loss of galactose binding affinity. These data suggest that the carbohydrate chains of ricin B chain may be required for full toxicity. The pathway of uptake of ricin by the macrophage mannose receptor was found to differ in several respects from uptake via the galactose-specific pathway. Analysis of intoxication of macrophages by ricin in the presence of ammonium chloride suggested that mannose receptor bound ligand passes through acidic vesicles prior to translocation, unlike galactose bound ligand. Intoxication by ricin via galactose-specific uptake was potentiated by swainsonine but not by castanospermine, suggesting that ricin may be attacked by an endogenous mannosidase within the cell, and that ricin passes through either a lysosomal or a Golgi compartment prior to translocation.

Ammonium Chloride↗
PubMed1986

Cytolytic T lymphocyte effector function requires plasma membrane chloride flux.

Treatment of cytotoxic murine T lymphocytes (CTL) with certain stilbene disulfonate derivatives results in a dose-related loss of lytic capacity. This effect is reversible and apparently not a function of drug toxicity. Additionally, CTL function is inhibited by isosmotic replacement of extracellular chloride with several relatively membrane-impermeable chloride analogues. Both inhibitory manipulations act on the effector rather than the target cell and are effective only during delivery of the lethal hit. These results suggest that delivery of the lethal hit may involve CTL exocytosis.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗