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D D Eardley

Publications and source records attributed to D D Eardley.

At least 37 records · Page 2Linked to original sources
PubMed1981

Immunoregulatory circuits that modulate responsiveness to suppressor cell signal. Failure of B10 mice to respond to suppressor factors can be overcome by quenching the contrasuppressor circuit.

The in vitro antibody response of spleen cells from B10 strain mice is not suppressed by factor preparations made by primed Ly-2 T cells, although these preparations can suppress the in vitro antibody response of spleen cells from other mouse strains (1-3)2. The factor preparations from Ly-2 cells contain at least two separable activities: one that acts as a suppressor moiety (Ly-2 T cell suppressor factor [Ly-2 TsF]) and a second factor that acts as an inducer of contrasuppression (Ly-2 TcsiF); the latter initiates a series of cellular interactions that leads to the inhibition of suppression that we refer to as contrasuppression. Removal of components (either cellular or humoral) of the contrasuppressor circuit makes spleen cells from B10 strain mice as easily suppressible as are those of other mouse strains. Thus, removal of the contrasuppressor inducer cell and/or its biologically active product with the use of an anit-J serum, or removal of the functional acceptor of the inducer cell with the same or other (Ly-2; Qa-1) antisera breaks the B10 suppressor barrier. Contrasuppressive activity. but not helper activity can be eluted from anit-I-J immunoabsorbents. The addition of B10 T cells to either B6 or B10 spleen cell culture deprived of acceptor cells for the TcsiF reconstitutes contrasuppression more efficiently than does the addition of C57BL/6 T cells. Ly-2 TcsiF is more cross-reactive than is Ly-2 TsF so that absorption of factor preparations from sheep erythrocyte-primed Ly-2 cells with horse erythrocytes also breaks the B10 suppressor barrier. The hyperresponsiveness of splenic T cells from B10 strains to Ly-2 TcsiF may be an in vitro exaggeration of a normal in vivo process. Thus it is possible that one can take advantage of this unusual situation to help dissect out the cellular and subcellular components of T cell circuits that moldulate sensitivity to immunoregulatory signals.

Animals↗
PubMed1981

Immunoregulatory circuits which modulate responsiveness to suppressor cell signals: characterization of an effector cell in the contrasuppressor circuit.

Spleen cells from neonatal animals, placed in culture for 6 days spontaneously develop the ability to block the activity of suppressor T cells, a phenomenon that is referred to as contrasuppression. The effector cell which is derived from the interactions among the cells which comprise a contrasuppressor "circuit" is an Ly-1 T cell. It can be separated from Ly-1 helper cells by three criteria other than function: its generation is dependent on Ly-2+ cells, it is I-J+, and it sticks to the Vicia villosa lectin. Those cells which deliver help to B cells under the experimental conditions studied are not dependent on Ly-2+ cells for generation and neither express determinants that our anti-I-J antisera recognize nor stick to V. villosa. The mechanism by which these Ly-1 contrasuppressor cells function was elucidated by adding them to "'intermediate cultures" containing activated Ly-2 suppressor cells and in vivo immunized Ly-1.1-congenic helper cells. After 48 h in these intermediate cultures, the neonatal Ly-1.2 contrasuppressor cells and the Ly-2 suppressor cells were removed by treatment with the appropriate antiserum plus complement. The remaining activity of the in vivo generated Ly-1.1 helper cells was assayed in fresh cultures of B cells. The contrasuppressor cells not only diminished suppression of the Ly-1 helper cells by the Ly-2 suppressor cells in the intermediate culture, but actually conferred a state of relative resistance to suppression upon the helper cells. This state persisted after the contrasuppressor cells were removed. Why such a cellular circuit, which confers resistance to suppression, might be beneficial to neonatal mice and how considering its attributes might help explain some immunological paradoxes is the subject of discussion.

Animals↗
PubMed1981

T cells in a suppressor circuit and non-T:non-B cells bear different I-J determinants.

T cells involved in the generation of suppressor activity bear an I-J-subregion controlled determinant (e.g., J1) which is distinct from that (e.g., J2) found on non-T:non-B accessory cells. T-cell subsets examined include Ly-1 inducer and Ly-1,2 acceptor cells which collaborate to generate suppressor activity in the in vitro sheep red blood cell antibody system. Non-T:non-B accessory cells examined include accessory cells involved in concanavalin-A induced, T-cell proliferative responses and in in vitro antibody responses to sheep red blood cells. These results provide evidence for serologic and genetic complexity of the I-J subregion of the murine H-2 gene complex.

Animals↗
PubMed1981

Functional deletion of different Ly-1 T-cell-inducer subset activities by Ly-2 suppressor T lymphocytes.

T-suppressor-cell activity was analyzed by use of an intermediate culture system that allows the study of T-cell interactions in the absence of concomitant inducer effects on B cells. Activated suppressor T cells were incubated with their potential target cells [immune Ly-1+,Ly-2- (Ly-1) cells] for 24-48 hr, and then the Ly-1 cells were reisolated by removing the suppressor cells with an appropriate antiserum (Ly-2). The functional consequences of the interactions that occurred during the incubation period were then assessed. Suppressor cells deleted the functional activity of two inducer-T-cell subsets; the helper T cell, which induces B-cell production of antibody, and the T cell that induces Ly2+ T suppressor cells. This latter activity is more sensitive to suppression than is the former. As suppressor T cells inactivate the cells that are responsible for their activity (i.e., their specialized Ly-1 inducer cells), a form of negative regulation of suppressor-T-cell activity, in which the down regulation of suppressor cells is effected by their removal of their own inducer cells, can be postulated. In addition, these findings show that clonal deletion and active suppression need not be mutually exclusive mechanisms of immune unresponsiveness. Suppressor cells can produce a functional deletion of immune activity that persists after they themselves are removed, for example, by antisera, or in physiological situations by the negative form of regulation postulated.

Animals↗
PubMed1980

Ly-1 inducer and Ly-1,2 acceptor T cells in the feedback suppression circuit bear an I-J-subregion controlled determinant.

An I-J-subregion controlled determinant is expressed on Ly-1 inducer and Ly-1,2 acceptor T cells in the feedback suppression circuit. Ly-1 T cells absorb the I-J antibody reactive with the Ly-1,2 acceptor T cell, suggesting that both inducer and acceptor T cells have the same I-J determinant. Since less than 10 percent of Ly-1 or Ly-1,2 T cells are killed by anti-I-J plus complement treatment, the I-J determinant demarcates functionally distinct subsets of both the Ly-1 and Ly-1,2 T-cell sets. This I-J determinant is not expressed on a detectable number of Ly-1 helper T cells which induce B lymphocytes to produce anti-sheep red cell antibody in tissue culture.

Animals↗
PubMed1980

Lymphotoxin production by subsets of T cells.

Lymphotoxin is produced by T cells sensitized to antigen upon re-exposure in vitro. It is also elicited by mitogen treatment. Its production has been correlated with delayed-type hypersensitivity and it may be a mediator of that phenomenon. We have examined the Ly phenotype of the subset(s) of T cells that produce lymphotoxin in order to investigate the relationship of lymphotokin killing to allo-killing mediated by Ly2+ T cells. We have found that Ly1 T cells sensitized to ovalbumin secrete more lymphotoxin than Ly2 cells. The ovalbumin-sensitized T cells do not lyse their target in a short term 51Cr-release assay even when "glued" to the target with Con A. Thus, lymphotoxin-producing cells differ phenotypically from the previously defined cytotoxic T cells that bear the Ly2 differentiation marker.

Animals↗
PubMed1980

Feedback suppression: an immunoregulatory circuit.

The basic elements of the feedback suppression circuit of T cell interactions are summarized. Ly1 T cells can be stimulated directly to become inducers of Ly2+ T suppressor cells or helper cells for B cells that produce antibody to erythrocyte antigens. Ly2 cells can be activated to become suppressors only in the presence of Ly1 cells. An Ly1,2,3, cell is the acceptor of the Ly1 inducer signal. Using an intermediate culture technique, it can be shown that Ly1 inducers are a target of suppressor T cell activity.

Antibody Formation↗
PubMed1979

Genetic control of immunoregulatory circuits. Genes linked to the Ig locus govern communication between regulatory T-cell sets.

Antigen-stimulated Ly1:Qa1+ cells induce a nonimmune set of T-acceptor cells (surface phenotype Ly123+Qa1+) to participate in the generation of specific suppressive activity. The experiments reported here were designed to test the possibility that the interaction between T-inducer and T-acceptor cells might be governed by genes linked to the Ig locus. We find that inducer:acceptor interactions occur only if the inducer and acceptor T-cell sets are obtained from donor that are identical at the Ig locus and are independent of the Ig locus expressed on the B cells used for assay of T-helper activity. In addition, experiments using inducer and acceptor T cells from the congenic recombinant BAB. 14 strain show that T-T interactions are not governed by Ig-CH genes, per se. These data indicate that T-inducer: T-acceptor interactions are governed by Ig-linked genes that may control expression of VH-like structures on T cells, or control expression of as yet unidentified cell-surface molecules.

Animals↗
PubMed1979

Induction of suppressor cells in rat spleen: influence of microbial stimulation.

The role of the products of prostaglandin synthetase in the suppression of in vitro secondary antibody responses by rat spleen cells was examined. By including cells from both germfree and conventional rats in these studies, the effect of in vivo microbial stimulation on this suppression was also determined. We found that 1) the suppression that is normally present in the spleen cells of rats can be eliminated by the use of glass wool or indomethacin; 2) germfree rats do not display this suppressor activity, and 3) this "deficit" in the germfree rat may be due to a lack of a microbial-induced signal from a nonadherent cell to an adherent prostaglandin-containing macrophage, implying that at least two cells are involved in the prostaglandin-synthetase dependent suppressor effect. It is possible that large amounts of some or all microbial products activate "suppressor" macrophages and that inbred rats behave like "chronically infected" mice because of an inability to regulate their "normal" microbial flora.

Animals↗
PubMed1979

Antigen-binding T cells: dose response and kinetic studies on the development of different subsets.

We have described a number of the parameters involved in the in vitro induction of specific SRBC-binding T cells (T rosette-forming cells, T-RFC). Although T-RFC precursors pass through nylon, most of the induced cells do not; nor do detectable numbers of Ly 1+2, 3- cells bind antigen with sufficient stability to form rosettes. The ratio of Ly 2,3:Ly 1,2,3 T-RFC varies with time after immunization and with the dose of antigen used for stimulation. Relatively high or low doses of antigen selectively induce Ly 1,2,3 T-RFC. Ly 2,3 T-RFC, when they appear, follow Ly 1,2,3 T-RFC. Pretreatment of T cells with anti-Ly sera before RFC induction prevents formation by Ly2+ T-RFC. Since anti-Ly 1 treatment blocks RFC formation and since Ly 1,2,3, T-RFC always precede the appearance of Ly 2,3, T-RFC, our results suggest that some Ly 1+ cells (Ly 123 at least, but perhaps also Ly 1) may act as inducers, precursors, and/or amplifiers for Ly 2,3 RFC as they appear to do for Ly 2,3 suppressor and killer cells. Thus, our results confirm and extend the observed similarities between T-RFC and other Ly 2+ cells such as killer and suppressor cells as well as their differences from Ly 1+ helper cells.

Animals↗
PubMed1979

Immunoregulatory circuits among T cell sets: effect of mode of immunization on determining which Lyl T cell sets will be activated.

Lyl T cells are able to induce B cells to make antibody and also to induce a resting Lyl23 T cell set to exert potent feedback suppression. Which of these two pathways Lyl T cells take can be influenced by the mode of immunization. In particular, in vitro immunized Lyl T cells are more likely to induce suppression than are Lyl T cells immunized in vivo even when both populations deliver the same amount of help to purified B cells. The feedback suppression induced by the Lyl T cells immunized in vitro can be distinguished from suppression mediated by Ly2+ T cells; in the former case suppression is preceded by a precocious antibody response, whereas suppression mediated by Ly2+ T cells is apparent throughout the entire period of observation.

Animals↗
PubMed1978

Immunoregulatory circuits among T-cell sets. Identification of a subpopulation of T-helper cells that induces feedback inhibition.

Purified Ly1 cells induce other T-cell sets to exert potent feedback inhibitory activity and this T-T interaction has been shown to play an important role in regulating in vivo immune responses. Approximately 2/3 of Ly1 cells also express the Qa1 surface phenotype (Ly1:Qa1+ cells). The experiments reported here indicate that Ly1:Qal+ cells are responsible for induction of feedback inhibition and that signals from both Ly1:Qal+ cells and Ly1:Qal- cells are required for optimal formation of antibody by B cells.

Animals↗
PubMed1978

Immunoregulatory circuits among T-cell sets. I. T-helper cells induce other T-cell sets to exert feedback inhibition.

These experiments test the hypothesis that cells carrying the Ly1+23- surface phenotype are programmed exclusively for helper and not suppressive activity regardless of external conditions such as the mode or type of antigen stimulation. To this end, we have stimulated purified populations of Ly1 cells with antigen in vitro using conditions devised to induce unselected T cells to express optimal levels of antigen specific T-suppressor activity. We find that after such stimulation, Ly1 cells generate SRBC-specific T-helper activity but not T-suppressive activity. These findings establish that the Ly1.2+,2.2/3.2- surface phenotype is a stable, and probably invariant, marker of T cells that are programmed to express only helper activity and have lost the capacity to directly suppress the antibody response. These findings support the concept that the genetic program for a single differentiated set of cells combines information for cell surface phenotype and function. We also demonstrate that antigen-stimulated Ly1 cells, in addition to inducing B cells to secrete antibody, can induce or activate other sets of resting T cells to develop profound suppressive effects. The surface phenotype of this feedback suppressive T-cell set is shown to be: Ly1+2+3+Qa1+. These findings, taken together, indicate that activation of resting Ly123 cells by immune Ly1 TH cells may represent an important homeostatic immunoregulatory mechanism.

Animals↗
PubMed1978

Association of defective feedback suppressor T cell activity with autoimmunity in NZB mice.

A "feedback suppressor T cell" highly dependent on signals from Ly 1 T helper cells for activation is described. The signal from the Ly 1 cell binds to Fc-like receptors on macrophage membranes. The feedback suppressor cell expresses all three Ly antigens as well as the Qa 1 antigen on its surface, is very sensitive to low doses of cyclophosphamide, disappears relatively rapidly after adult thymectomy, and cannot be demonstrated in NZB mice 6 weeks or older.

Age Factors↗
PubMed1978

Activation of distinct helper and suppressor T cells in experimental trypanosomiasis.

Spleen cells taken from mice soon after infection with Trypanosoma brucei S 42 enhance the primary in vitro antibody response of normal spleen cells to sheep red blood cells (SRBC), but do not affect their response to DNP-Ficoll. Spleen cells harvested later in the infection (day 6 onwards) suppress the antibody response of normal spleen cells to both SRBC and DNP-Ficoll. The enhancing and suppressive effects of "infected" spleen cells are sensitive to treatment with anti-Thy 1.2 anti-serum and complement, and can be mediated by nylon wool-purified populations of T cells. The enhancing T cell is sensitive to ALS, not lost within 4 weeks of adult thymectomy, and bears the Ly-1+, 23- phenotype. The suppressor T cell is insensitive to ALS, lost within 20 weeks of adult thymectomy, and bears the Ly-1+, 23+ phenotype. The significance of the activation of distinct helper and suppressor T cells is discussed in relation to the pathogenesis of trypanosomiasis.

Animals↗
PubMed1977

Suppressor cells in mice infected with Trypanosoma brucei.

Within 2 to 3 days of infection with Trypanosoma brucei strain S42, the ability of spleen cells from infected CBA mice to mount a primary in vitro antibody response to sheep red blood cells (SRBC) is profoundly reduced, and suppressor cells are generated as detected by cell mixture experiments. Suppressor cell activity lies in the T and adherent cell compartments of spleens from infected mice, but not in the B cell compartment, although antibody responses to a thymus-independent antigen, DNP-Ficoll, are significantly reduced. Suppression of antibody responses of normal spleen cells depends on viable cells from infected mice. The trypanosome, itself, plays no direct role in suppression, and we have ruled out the possibility of antigenic competition as a mechanism of suppression. Our data is consistent with the model of suppressor T cells induced by concanavalin A mitogenesis. We hypothesize that trypanosome antigens may directly stimulate T cells with the concomitant release of factors with affinity for macrophage surfaces thus becoming suppressive for T and B cell responses.

Animals↗