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R J Mogil

Publications and source records attributed to R J Mogil.

10 recordsLinked to original sources
PubMed1995

Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas.

A number of murine T-cell hybridomas undergo apoptosis within a few hours of activation by specific antigens, mitogens, antibodies against the T-cell antigen receptor, or a combination of phorbol ester and calcium ionophore. This phenomenon has been extensively studied as a model for clonal deletion in the immune system, in which potentially autoreactive T cells eliminate themselves by apoptosis after activation, either in the thymus or in the periphery. Here we show that the Fas/CD95 receptor, which can transduce a potent apoptotic signal when ligand, is rapidly expressed following activation of T-cell hybridomas, as is its functional, membrane-bound ligand. Interference with the ensuing Fas/Fas-ligand interaction inhibits activation-induced apoptosis. Because T-cell receptor ligation can induce apoptosis in a single T hybridoma cell, we suggest that the Fas/Fas-ligand interaction can induce cell death in a cell-autonomous manner.

Animals↗
PubMed1995

Fas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo.

Following exposure to some types of antigen (superantigens), responsive T cells expand and then decline in numbers, a phenomenon that has been called 'peripheral deletion'. This process may play a role in limiting autoimmune reactions and in the maintenance of immune homeostasis. Here we describe experiments on peripheral deletion in mice carrying the lpr/lpr defect, which has been shown to be due to defective production of the CD95/Fas molecule. Young lpr/lpr mice with no apparent immunologic abnormalities display a defect in bacterial superantigen-induced peripheral deletion. Apoptotic death of the expanded T cell population associated with such peripheral deletion. Apoptotic death of the expanded T cell population associated with such peripheral deletion in normal animals is dramatically reduced in the mutant mice. Further, the levels of Fas on responding cells in normal mice increases and decreases together with increases and decreases in cell numbers, suggesting that cells with the highest levels of Fas are preferentially deleted. These observations are consistent with the known ability of CD95 to transduce a signal leading to apoptosis, and they implicate this signal transduction pathway in peripheral deletion. In contrast, bacterial superantigen-induced deletion of thymocytes appears to be fully functional in these mice, and thus Fas/APO-1 does not appear to be required for this process. Further, antibody ligation of the TCR on activated T cells from normal or young lpr/lpr mice can induce apoptosis and therefore under some circumstances this phenomenon is not dependent upon CD95/Fas. Thus, to avoid autoreactivity and ensure immune homeostasis, several different apoptotic mechanisms exist in peripheral T lymphocytes, only some of which involve Fas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Role of DNA fragmentation in T cell activation-induced apoptosis in vitro and in vivo.

Apoptotic cell death, characterized by DNA fragmentation and morphologic changes, has previously been shown to occur in immature thymocytes and some T cell hybridomas after activation. Like some other forms of apoptosis, DNA fragmentation during activation-induced cell death precedes the morphologic events. For apoptosis to proceed, activation of the cells must persist at least to the time of DNA fragmentation, before which the cells can remain viable if the activation signal is removed. Aurintricarboxylic acid (ATA) blocks activation-induced apoptotic cell death in a T cell hybridoma, and kinetic studies show that this inhibition occurs at or near the time of DNA fragmentation in the cells. Taken together with the ability of ATA to inhibit DNA fragmentation in isolated nuclei exposed to Ca2+ and Mg2+, these data strongly suggest that ATA prevents apoptosis via its ability to inhibit endogenous endonuclease activity, and, conversely, that this activity is required for this form of cell death. In vivo, ATA inhibits thymocyte depletion and DNA fragmentation induced by anti-CD3 Ab. Further, specific loss of V beta 8+ thymocytes after administration of staphylococcal enterotoxin B is blocked by administration of ATA. These observations support an essential role for DNA fragmentation as an irreversible step in activation-induced apoptosis in T cell hybridomas and during T cell development. This is contrasted with heat shock-induced cell death, in which inhibition of DNA fragmentation does not prevent loss of cell viability.

Animals↗
PubMed1991

Immunoregulatory activity of the T-cell receptor alpha chain demonstrated by retroviral gene transfer.

We have previously described an antigen-specific I-Ad-restricted T-cell hybridoma, A1.1, that constitutively releases an antigen-specific immunoregulatory activity into supernatants. Using retrovirally mediated gene transfer, we have found that transfer of the T-cell receptor alpha chain (TCR alpha) gene from A1.1 to a number of other T-cell hybridomas effectively transferred the ability to produce the activity. Gene transfer of the TCR beta chain (TCR beta), however, did not transfer this ability. The regulatory activity from cells expressing the A1.1 TCR alpha bound to and was eluted from an anti-TCR alpha monoclonal antibody and displayed fine antigenic specificity identical to that of supernatants from A1.1. The possibility that this activity represents a secreted form of the TCR alpha (as opposed to shed cell-surface TCR) was examined in BW1100 cells, lacking TCR alpha and TCR beta, which produced the antigen-specific activity after gene transfer of the A1.1 TCR alpha gene. The expression of the immunoregulatory activity in supernatants correlated with a direct antigen-binding activity as detected by ELISA, thus raising the possibility that antigen binding is relevant to the mechanism of action of the soluble TCR alpha. We discuss these observations and our earlier studies suggesting an immunoregulatory role for soluble TCR alpha.

Amino Acid Sequence↗
PubMed1989

Kinetics of murine delayed-type hypersensitivity response to Eimeria falciformis (Apicomplexa: Eimeriidae).

Mice recovering from a primary infection with an intestinal protozoan parasite, Eimeria falciformis (Apicomplexa: Eimeriidae), showed a classic delayed-type hypersensitivity (DTH) reaction to oocyst antigen challenge. This reaction was characterized by a biphasic pattern of footpad swelling. The first swelling peaked at 2 h after antigen challenge, whereas the second swelling peaked at 24 to 48 h after challenge. The DTH reaction was transferable with a T-cell-enriched spleen cell population from mice that had recovered from E. falciformis infection. Cytotoxic depletion of immune T cells with anti-L3T4 antibody and complement abrogated DTH transfer, indicating that L3T4-positive T cells were required. A T-cell-enriched spleen cell population from acutely infected mice suppressed the transfer of DTH with immune cells from recovered animals, implicating the existence of infection-induced immunoregulatory cells controlling the parasite-specific immune response during infection. Immune spleen cells also transferred resistance to infection as measured by oocyst production and death rate of recipients. Together, these results indicate that the DTH reaction, induced by infection with E. falciformis, is mediated by L3T4-positive T cells and is associated with resistance to infection.

Acute Disease↗
PubMed1988

An immunogenic antigen of murine Plasmodium yoelii 17X associates with class I MHC glycoproteins.

Reticulocytes infected with the non-lethal variant of Plasmodium yoelii 17X (PY17X-NL) express elevated levels of class I, but not class II, MHC Ag when compared with non-parasitized reticulocytes. In contrast, class I Ag are not detectable on erythrocytes parasitized by the lethal variant PY17X-L. In addition, the responder status of various inbred strains of mice to PY17X-NL has been shown to positively correlate with the levels of class I MHC antigens expressed on PY17X-NL parasitized red blood cells (PRBC). MHC Ag are known to restrict, or guide, immune responses. However, earlier studies have failed to demonstrate H-2 restricted activity in the effector arm of immunity to blood-stage murine malaria. Therefore, we have examined the induction of immunity by irradiated PY17X-NL PRBC. No MHC restriction was observed in the ability of PRBC to immunize recipients. However, using irradiated PRBC bearing low, intermediate or high levels of class I Ag we found that the levels, rather than haplotype, of class I Ag expressed on irradiated PRBC greatly influenced their ability to induce immunity. Furthermore, class I-associated parasite-directed Ag were isolated as an immunogenic complex with anti-class I MHC antibody. Such complexes induced immunity in vivo in the absence of adjuvant suggesting a biologically important mechanism by which non-lethal, reticulocytic forms of malarial parasites may immunize their hosts.

Animals↗
PubMed1987

Cellular subsets involved in cell-mediated immunity to murine Plasmodium yoelii 17X malaria.

Cell mediated immunity to nonlethal Plasmodium yoelli 17X (PY17X-NL) was examined in the CBA/CaJ mouse by adoptive transfer of sensitized T lymphocyte subsets. In intact mice, PY17X-NL causes a self-limiting infection with parasitemia levels ranging from 10 to 25% of total red blood cells. Upon recovery, mice are refractory to subsequent challenge with the homologous parasite. In T cell-depleted mice, PY17X-NL infections are extremely virulent and result in death of the host after parasitemia levels reach 50% or higher. The transfer of either Lyt-1 T cells or Lyt-2 T cells from immune animals into normal, naive animals produced accelerated recovery to subsequent infection. However, this adoptive transfer of immunity by either subset was dependent upon the presence of an I-J+, Lyt-null cell in the immune population. T cell deprivation precluded the ability of animals to control blood-stage infections. When T cell-depleted mice were reconstituted with naive, Ig-negative (T cell-enriched) spleen cells, parasitemia levels were controlled and the parasites were eliminated. When T cell-deprived animals were reconstituted with naive Lyt-1+2-, Ig-negative spleen cells, they experienced twofold higher parasitemias of longer duration than mice receiving unfractionated cells. Two of six of these Lyt-1 mice died of fulminant infections, suggesting that the presence of naive Lyt-2 cells enhances the degree of protection. Immune Lyt-2 T cells were highly protective in T cell-depleted animals. Protection by sensitized Lyt-1 T cells correlated with the induction of a monocytosis. On the other hand, protection by Lyt-2T cells occurred in the absence of monocytosis. The possibility that the immunity induced by each T cell subset is mediated by a different effector mechanism is discussed.

Animals↗
PubMedDate not supplied

Immunoregulatory effects of lymphokine-driven placental cells on cloned T cells in vitro.

Successful pregnancy is associated with maternal immune sensitization to placental antigens. Placental trophoblast cells at the maternal-fetal interface express histocompatibility antigens of both the maternal and paternal haplotypes. In particular, these paternal-type antigens have the potential to stimulate alloreactive maternal immune responses and, as a result, maternal T cells appear in the decidua shortly after class I major histocompatibility complex encoded antigens are expressed. Despite this maternal immune recognition, immunologic destruction of the fetus rarely occurs. In fact, recent evidence suggests that the interaction between maternal T cells and placental cells results in an "immunotrophic" effect that stimulates placental growth and fetal survival. To better understand the contribution of fetally derived placental cells in the activation of maternal immunity, we have developed a murine lymphokine-dependent long-term placental cell line termed "FRD." FRD cells can stimulate syngeneic, semi-syngeneic, and allogeneic murine spleen cells to proliferate in a mixed lymphocyte-placental cell reaction. Coculture experiments with T hybridomas show that unlike conventional antigen-presenting cells, FRD can activate T cells to secrete lymphokines in the absence of specific antigen. In addition, lymphokine-activated FRD cells release factors that directly stimulate proliferation of the IL 1 responsive T cell line D10.G4.1. These observations suggest that placental cells stimulate T cells via novel mechanisms that may play a role in producing a maternal T cell response that in turn is beneficial to fetally derived tissues during pregnancy.

Animals↗