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J H Russell

Publications and source records attributed to J H Russell.

At least 37 records · Page 2Linked to original sources
PubMed1995

Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77).

T cell hybridomas require the immediate-early gene NGFI-B (nur77) for T cell receptor (TCR)-mediated apoptosis, a model for negative selection of self-reactive T cells. TCR-mediated death was examined in mice bearing an NGFI-B loss-of-function mutation, either by administration of antibodies to CD3 (anti-CD3) or in two well-characterized transgenic models expressing self-reactive TCRs. Both the extent and the rate of thymocyte death were unimpaired. Anti-CD3-induced death was normal in CD4+ peripheral T cells, in which death is mediated predominantly by the Fas signaling pathway. Thus, no unique requirement for NGFI-B is observed for thymic or peripheral T cell death.

Animals↗
PubMed1995

Natural killer and lymphokine-activated killer cells require granzyme B for the rapid induction of apoptosis in susceptible target cells.

Granzyme (Gzm) B-deficient mice obtained by gene targeting were used to assess the role of Gzm B in the mechanisms used by natural killer (NK) and lymphokine-activated killer (LAK) cells to destroy target cells. Gzm B-/- NK cells, LAK cells, and cytotoxic T lymphocytes (CTL) all are defective in their ability to rapidly induce DNA fragmentation/apoptosis in susceptible target cells. This defect can be partially corrected with long incubation times of effector and target cells. Moreover, Gzm B-/- NK cells (but not CTL or LAK cells) exhibit a defect in 51Cr release from susceptible target cells. This 51Cr release defect in Gzm B-deficient NK cells is also not overcome by prolonged incubation times or high effector-to-target cell ratios. We conclude that Gzm B plays a critical and nonredundant role in the rapid induction of DNA fragmentation/apoptosis by NK cells, LAK cells, and CTL. Gzm B may have an additional role in NK cells (but not in CTL or LAK cells) for mediating 51Cr release.

Amino Acid Sequence↗
PubMed1995

Apoptotic death of lymphocytes in murine acquired immunodeficiency syndrome: involvement of Fas-Fas ligand interaction.

Murine acquired immunodeficiency syndrome (MAIDS) is caused by a defective murine leukemia virus. The disease is characterized by abnormal lymphoproliferation, impaired T and B cell function and aberrant regulation of cytokines. Both T and B lymphocytes show activated phenotypes, but undergo apoptotic death with characteristic DNA fragmentation. These results indicate the presence of a continuous activation death pathway of the lymphocytes in MAIDS. Overexpression of the bcl-2 transgene in lymphocytes showed no effect on the apoptotic cell death or on the development of the disease. In contrast, mice carrying mutations in either Fas or Fas ligand exhibited accelerated progression of the disease upon infection with MAIDS virus. These results suggest the involvement of Fas-Fas ligand system in the pathogenesis of MAIDS.

Animals↗
PubMed1995

Macrophage apoptosis in the absence of active interleukin-1 beta-converting enzyme.

The interleukin-1 beta converting enzyme (ICE) is the cysteine proteinase responsible for cleaving the 31-kDa interleukin-1 beta (IL-1 beta) precursor to its active 17-kDa form. In lipopolysaccharide-stimulated cultured macrophages, induction of apoptosis but not necrosis effectively induces conversion of the IL-1 beta precursor to its mature form and results in the concomitant release of the mature cytokine from the cell. To determine whether ICE activity is required for macrophage apoptosis, we have exposed macrophages either to 5 mM ATP or to alloreactive cytolytic T lymphocytes (CTL) in the absence and presence of the ICE inhibitor peptide YVAD-chloromethylketone (YVAD-emk). Activated cells treated with YVAD-emk and ATP or CTL showed no mature IL-1 beta in either the cell lysates or the culture supernatants, indicating effective inhibition of ICE activity; however, the YVAD-treated macrophages showed no detectable change in 51Cr release or nuclear fragmentation, indicating failure to inhibit apoptotic cell death. Thus, in these cells, YVAD-emk uncouples IL-1 beta processing and apoptosis.

Adenosine Triphosphate↗
PubMed1995

Role of the immune response in interstitial cystitis.

Interstitial cystitis (IC) patients present with irritative and painful bladder symptoms and are diagnosed clinically by their symptoms, negative urine cultures, absence of other diseases, and cytoscopic findings of glomerulations and/or ulcers. The histological evaluation usually is described as nonspecific chronic inflammation. Although numerous theories of pathogenesis have been proposed, the etiology of IC is unknown. The hypothesized causes of IC include infectious, lymphovascular obstruction and neurogenic, endocrinologic, psychoneurotic, inflammatory (especially mast cells), and autoimmune pathologies. In this Review we discuss the evidence supporting a role for autoimmunity in IC and link the mast cell to the expression of the disease. Moreover, we discuss newly developed animal models that may provide insight into the etiology of IC.

Animals↗
PubMed1995

Activation-induced death of mature T cells in the regulation of immune responses.

Deletion of self-reactive clones of immature thymocytes by activation-induced death (AID) is thought to be the primary mechanism for the establishment of self-tolerance in the T-cell compartment. Recent evidence suggests that a genetically distinct but analogous process of AID in mature T cells is important in regulating peripheral immune responses. AID of peripheral T cells requires the expression of functional Fas and Fas ligand by the T-cell population. As qualitatively similar signals from the TCR are responsible for both T-cell expansion in inflammation and T-cell elimination by AID, regulating the balance between these opposing functions plays a crucial role in successful responses to pathogens and tumors while minimizing autoimmunity.

Animals↗
PubMed1994

Heterogeneity of single cell cytokine gene expression in clonal T cell populations.

T helper type 0 (Th0), Th1, and Th2 CD4+ T cell clones derived from a T cell receptor alpha/beta (TCR-alpha/beta) transgenic mouse were activated by antigen presented on "artificial" antigen-presenting cells that expressed or lacked the costimulatory molecule B7-1, and were analyzed for single cell cytokine mRNA expression by in situ hybridization. There was significant heterogeneity in the frequency of T cells that expressed individual cytokine mRNAs within each clonal population, suggesting that transcriptional control of each of the cytokine genes was not coordinate within an individual cell. The majority of antigen-stimulated Th1 cells expressed mRNA for interferon gamma (IFN-gamma), but far fewer cells in the same population expressed interleukin 2 (IL-2). Similarly, the frequency of IL-4-expressing cells was greater than that of IL-5- or IL-10-expressing cells in the same Th2 population, but the difference in expression frequencies was more variable between clones. The expression frequencies of each of the cytokines was quite heterogeneous in the antigen-activated Th0 population. The principal effect of increased antigen on the activation of individual cytokine genes in each of the clonal populations was to increase recruitment of mRNA-positive cells, with little or no effect on the level of cytokine mRNA expression in individual positive cells. The effects of B7 costimulation were variable depending on the cytokine gene analyzed. B7 costimulation markedly increased the frequency and the level of IL-2 mRNA expression in individual positive cells in the Th1 and Th0 populations, with less effect on the recruitment and single cell expression level of IFN-gamma. IL-4 frequencies were modestly increased by B7 costimulation of the Th2 clones, but there was no detectable increase in single cell IL-4 expression level. The observed patterns of cytokine mRNA expression favor a model of T cell activation in which all-or-none, rather than graded, responses of cytokine genes are dominant.

Animals↗
PubMed1994

Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells.

We have generated H-2b mice with a homozygous null mutation in the granzyme (gzm) B gene. Gzm B is a neutral serine protease with Aspase activity that is found only in the granules of activated cytolytic T cells, natural killer cells, and lymphokine-activated killer cells. Gzm B-/- mice develop normally and have normal hematopoiesis and lymphopoiesis. In vitro, cytotoxic T lymphocytes (CTL) derived from gzm B-/- animals are able to induce 51Cr release from allotarget cells, but with reduced efficiency. However, gzm B-/- CTL have a profound defect in their ability to induce rapid DNA fragmentation and apoptosis in allogeneic target cells. This defect is kinetic since DNA fragmentation is partially compensated and 51Cr release is completely rescued with long incubation times. We conclude that gzm B serves a critical and nonredundant role for the rapid induction of target cell DNA fragmentation and apoptosis by alloreactive cytotoxic T lymphocytes.

Animals↗
PubMed1993

Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide.

Antigen receptor-stimulated cell death of developing, immature T cells plays an important role in shaping the repertoire of antigens to which mature T cells will respond, but a role for receptor-stimulated death in controlling responses of mature T cells is controversial. Mutant lpr/lpr mice exhibit an autoimmune syndrome similar to systemic lupus erythematosus. Here we demonstrate that these mice have a defect in antigen-stimulated suicide of activated T cells in mature CD4+ and CD8+ T cell compartments. The defective suicide pathway is evident when the T cells are stimulated with antigen on antigen-presenting cells or with immobilized anti-CD3 in the absence of antigen-presenting cells. These studies, in concert with the work of others, suggest that antigen-stimulated death of mature cells may be important both in establishing peripheral tolerance and in limiting inflammation during normal immune responses.

Animals↗
PubMed1993

Differential activation of antigen-stimulated suicide and cytokine production pathways in CD4+ T cells is regulated by the antigen-presenting cell.

Stimulation of the TCR of activated, mature T cells by an APC produces a spectrum of functional responses. Most of those responses positively promote immunity and inflammation. However, death of the responding T cell, which would limit subsequent inflammation, can also result from such stimulation. We compare the Ag threshold necessary to promote inflammation through cytokine production with the Ag threshold necessary to limit inflammation through T cell death. These two responses are independently regulated by the APC and this regulation is selective for both different APC products and different T cell subsets. The costimulator B7 selectively decreases the Ag threshold for cytokine production in Th1 cells with no effect on the Ag threshold for Th1 death. B7 has no effect on the Th2 Ag threshold for cytokine production or death. In contrast, IFN-gamma negatively modulates a macrophage product that selectively increases the threshold of Ag necessary to stimulate death in Th2 cells, but has no effect on cytokine production by Th2 cells or cytokine production or death of Th1 cells. This selective regulation of cytokine production and T cell death may play an important role in both shaping the quality of a given immune response and in providing a general mechanism for the regulation of the immune response by limiting inflammation and through peripheral deletion of inappropriate T cell specificities.

Animals↗
PubMed1993

Autoimmune gld mutation uncouples suicide and cytokine/proliferation pathways in activated, mature T cells.

Antigen receptor-directed suicide plays an important role in the elimination of potentially autoaggressive immature T cells during thymic differentiation. Here we demonstrated evidence for a second pathway of receptor-directed suicide in mature T cells that is missing in a mutant strain (gld) of mice with an "autoimmune" lymphoproliferative syndrome. The defect is evident within the gld activated T cell and does not require the presence of an antigen-presenting cell for its expression. Receptor-driven suicide is intact in immature T cells of animals with this mutation. These results support the significance of receptor-directed suicide in the mature T cell compartment and suggest that the immune system may use three independent pathways for regulating programmed cell death in shaping and controlling the immune response.

Animals↗
PubMed1993

Detachment and lysis of adherent target cells by CD4+ T cell clones involve multiple effector mechanisms.

Detachment of adherent targets from their substratum is a unique activity of both CD8+ and CD4+ T cells. Recently, we have demonstrated that with mixed, alloreactive populations, CD4+ T-cell-mediated detachment is kinetically distinct from lysis and requires protein synthesis. Heterogeneity of effector phenotypes precluded further elucidation of the mechanism of detachment at the mixed population level. Here, we examine further the mechanism of target cell detachment by CD4+ cells using clones which differ in lytic efficiency and demonstrate that detachment of adherent targets from their substratum (1) may result from either protein synthesis-dependent or independent pathways, which can be correlated with differences in clonal lytic phenotype, (2) is contact dependent and does not involve soluble factors, (3) can be pharmacologically uncoupled from IL4 production, as a measure of cytokine release, and (4) fails to correlate with perforin expression by immunocytochemistry. Finally, isolated granule preparations are unable to mediate detachment independent from lysis.

Animals↗
PubMed1993

Separation of CD4+ functional responses by peptide dose in Th1 and Th2 subsets expressing the same transgenic antigen receptor.

CD4+ T cells from alpha beta-TCR transgenic mice were used to explore the effect of antigen dose on various functional activities. This transgenic system provides for a source of antigen-specific T cells with the same TCR which can develop into Th1 and Th2 phenotypes under controlled conditions. Of particular interest was to determine if detachment of adherent targets from their substrate could be separated from other functional activities by either antigen dose or functional subset. Using this model, we have found that (a) Th1 and Th2 phenotypes exhibit a similar peptide dose-dependent pattern of detachment and lysis, although Th2 are generally less lytic on both fibroblast and lymphoma targets; (b) detachment and lysis can be dissociated from cytokine production by low peptide doses; (c) detachment and lysis can be physiologically as well as temporally and pharmacologically uncoupled as most targets recovered after detachment by Th2 effectors retain their capacity to proliferate.

Animals↗
PubMed1991

Receptor-stimulated death pathway is opened by antigen in mature T cells.

Clonal deletion provides an important mechanism for the elimination of autoreactive T cells. Deletion is accomplished by programmed cell death directed by interaction of the T-cell receptor (TCR) of the developing thymocyte with major histocompatibility complex elements in the thymic environment. In this report we present evidence to support the hypothesis that the activation and the maturation state of the T cell may be important in coupling the TCR to the "death program." We show that coupling of the TCR to the death program is open during maturation but closed in naive mature T cells. However, during primary antigenic stimulation, coupling between the TCR and the death program is reopened, as demonstrated by the stimulation of the death of these cells by immobilized anti-TCR. Our results suggest that further examination of mature cells that are either resistant or sensitive to receptor-stimulated death may lead to the identification of the components of the death pathway and may provide clues to the regulation of their coupling to TCR signals.

Animals↗
PubMed1991

CD4+ T lymphocyte-induced target cell detachment. A model for T cell-mediated lytic and nonlytic inflammatory processes.

We have been exploring the hypothesis that T lymphocytes have the potential to mediate immune damage through nonlytic disruption of tissue organization. In this report, we have examined the ability of purified, primary cultures of alloreactive CD4+ T cells to mediate Ag-specific target cell detachment and/or lysis of L cell lines transfected with MHC class II determinants. Using this model, we demonstrate that: 1) MHC class II-specific CD4+ T cells can cause detachment as a distinct event of the E:T interaction, although the pathways or mechanisms involved appear to be different from those utilized by MHC class I-specific CD8+ T cells; 2) detachment and lysis by CD4+ T cells are distinct activities that involve different functional requirements: 3) CD4+ T cell-induced detachment is initiated by direct cell-cell interaction, independent of TNF-alpha/beta; 4) CD4+ T cell-mediated lysis can be accomplished by TNF-alpha/beta-dependent and independent pathways; and 5) the nature of a particular target cell response to alloreactive CD4+ T cell attack reflects its intrinsic susceptibility to one or more potential effector mechanisms.

Animals↗