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P C Marrack

Publications and source records attributed to P C Marrack.

17 recordsLinked to original sources
PubMed1999

Reactive oxygen species regulate activation-induced T cell apoptosis.

Reactive oxygen species (ROS) mediate apoptosis in a number of cell types. We studied the role that ROS play in activated T cell apoptosis by activating T cells in vivo and then culturing them for a short time. Activated T cells died independently of Fas and TNF alpha. Their death was characterized by rapid loss of mitochondrial transmembrane potential (delta psi(m)), caspase-dependent DNA fragmentation, and superoxide generation. A superoxide dismutase mimetic, Mn (III) tetrakis (5, 10, 15, 20-benzoic acid) porphyrin (MnTBAP), protected T cells from superoxide generation, caspase-dependent DNA loss, loss of delta psi(m), and cell death. These results indicate that ROS can regulate signals involved in caspase activation and apoptosis and may contribute to peripheral T cell deletion.

Animals↗
PubMed1994

Thymic epithelial cell lines that mediate positive selection can also induce thymocyte clonal deletion.

Negative selection of potentially autoreactive thymocytes occurs mainly in the thymus and is thought to be induced primarily by interaction with bone marrow-derived cells. However, some studies have also reported a role for radioresistant thymic cells, which are probably epithelial in origin, in the deletion of thymocytes reacting to endogenous superantigens. We have previously demonstrated that thymic epithelial cell lines could induce thymocyte-positive selection in vivo. In this study, we assessed the potential of these cells to delete thymocytes reacting to the staphylococcal enterotoxin A or B superantigens in vitro. In the presence of staphylococcal enterotoxin A or B we found that all thymic epithelial cell lines used in this study were capable of activating T cell hybrids or deleting CD4+CD8+ thymocytes expressing an appropriate TCR. The extent of superantigen-mediated thymocyte deletion mediated by thymic epithelial cell lines was comparable to that mediated by a thymic macrophage cell line. Similar results were obtained with three phenotypically distinct thymic cell lines, suggesting that the ability to induce thymocyte deletion might be a general feature of various subsets of thymic epithelium. The observations provided in this study, combined with our previous demonstration that the same thymic epithelial cell lines can participate in positive selection, suggest that a given stromal cell population might be capable of taking part both in positive and negative selection of thymocytes.

Animals↗
PubMed1993

Profound deletion of mature T cells in vivo by chronic exposure to exogenous superantigen.

It has been noted previously that superantigens can under different circumstances stimulate activation, expansion, anergy, and/or deletion of reactive T cells in vivo and in vitro. Here, we present a detailed examination of the expansion and deletion of T cells in vivo in response to the superantigens staphylococcal enterotoxin A (SEA) in the B10.BR mouse. Mice were either acutely or chronically exposed to varying doses of SEA, and the relative level of T cells bearing SEA-reactive V beta elements was followed over time in lymphocytes purified from peripheral blood, lymph nodes, mesenteric lymph nodes, and spleen. In most cases, an initial sharp rise in the proportion of reactive T cells was followed by a dramatic decline. Cells of the CD4+ and CD8+ lineages displayed subtle differences in their kinetics of activation and deletion, as well as their sensitivity to different doses of SEA. Furthermore, cells bearing either of two V beta elements previously characterized as SEA-reactive showed some differences in their responses to SEA treatment. Acute exposure usually caused the disappearance of only 50% to 70% of reactive T cells; however, chronic exposure to SEA caused almost complete deletion of target T cells. Deletion was evident even in animals treated with very low doses of SEA, doses that were too small to cause any apparent T cell proliferation. Thus, proliferation does not appear to be a prerequisite for peripheral deletion of T cells.

Animals↗
PubMed1992

A cell line that can induce thymocyte positive selection.

The thymus positively selects thymocytes that bear T-cell receptors which recognize antigen presented by self major histocompatibility complex (MHC) proteins. Positive selection is usually driven by MHC products on radiation-resistant cortical epithelial cells. It is unknown whether positive selection is mediated by all thymic epithelial cells or by some specialized subsets. Here we introduce an H-2b-expressing thymic epithelial cell line into the thymuses of lethally irradiated H-2k animals reconstituted with H-2b/k F1 BM or fetal liver cells. I-Ab-restricted T cells are found in these animals, demonstrating that selection occurs on the introduced epithelial cells.

Animals↗
PubMed1992

Immature thymocytes are protected from deletion early in ontogeny.

Self/non-self discrimination occurs within the thymus, where T cells undergo positive selection to produce a repertoire that recognizes foreign antigen in the context of self major histocompatibility complex proteins and negative selection to eliminate from the repertoire those T cells with self-reactive specificities. We have previously shown that two subpopulations of immature antigen receptor-bearing thymocytes exist, one that is susceptible to negative selection induced by ligation of the T-cell receptor for antigen and a second that is resistant to T-cell receptor-mediated negative selection. In the current work, we show that all antigen receptor-bearing thymocytes in early fetal thymuses are resistant to negative selection and that thymocytes susceptible to deletion do not develop until later gestational ages. Thus, deletion is a relatively late event in T-cell ontogeny. In addition, these data suggest that a thymocyte population can be isolated early in ontogeny that is capable of transducing selective signals through the antigen receptor, which do not lead to deletion but may result in positive selection.

Animals↗
PubMed1989

T cell tolerance to self antigens in New Zealand hybrid mice with lupus-like disease.

We determined if self-reactive T cells are able to escape thymic tolerance in autoimmune New Zealand mice. T cells utilizing V beta 17a and V beta 11 encoded receptors have been shown to be clonally eliminated in nonautoimmune mice expressing I-E because of their potential self-reactivity. Similarly, V beta 8.1+ and V beta 6+ T cells are tolerized in the thymus of nonautoimmune mice that express Mls-1a. These T cell subsets were quantitated in the lymph nodes and spleens of (NZB x NZW)F1 and (NZB x SWR)F1 mice. In young mice from both autoimmune strains, deletion was similar to that observed in control animals matched for I-Ed and Mls-1a expression. Furthermore, older female autoimmune mice with elevated levels of IgG antinuclear antibodies and severe lupus-like renal disease did not demonstrate evidence of a global tolerance defect. We also found that the levels of residual V beta 17a+ cells in MHC-matched control F1 strains were further reduced by up to 80% in autoimmune (NZB x SWR)F1 mice. The greater in vivo elimination corresponded to an enhanced ability of NZB spleen cells, compared with other H-2d spleen cells, to stimulate V beta 17a+ hybridomas in vitro. The increased stimulation in culture could not be attributed to quantitative differences in I-E Ag expression. The results suggest that autoreactive T cells have been eliminated in these autoimmune mice by normal mechanisms of self-tolerance. Furthermore, the data demonstrate the existence of an NZB minor locus not present in other H-2d strains that influences T cell repertoire and enhances stimulation of T cells potentially reactive to self class II MHC Ag.

Animals↗
PubMed1988

Molecular basis for the nonexpression of V beta 17 in some strains of mice.

The TCR alpha/beta variable element V beta 17a is expressed in all strains of mice carrying the V beta a complex in which about half of the V beta elements have been lost due to a large deletion. The mAb KJ23a detects V beta 17a containing alpha/beta receptors in these mice. Mouse strains with the V beta b complex carry a full complement of V beta genes including a structural gene for V beta 17 (V beta 17b), but no T cells reactive with KJ23a are present in these mice. Among random peripheral T cell hybridomas prepared from V beta b mice, occasional V beta 17b transcripts are found. The sequence of one of these transcripts reveals a single base difference from V beta 17a which results in a termination codon within the coding region inactivating the gene.

Amino Acid Sequence↗
PubMed1988

Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex.

In mice the product of the Mlsa locus is an unusual antigen capable of interaction with certain products of the major histocompatibility locus (MHC) to form a ligand for a large portion of the T-cell alpha/beta receptor repertoire, including nearly all receptors that use V beta 8.1. The presence of Mlsa/MHC during T-cell development results in the deletion of T cells that express V beta 8.1, documenting the importance of clonal deletion in establishing tolerance to self antigens.

Animals↗
PubMed1981

Analysis of the response of B cells from CBA/N-defective mice to nonspecific T cell help.

We have investigated the induction of antibody responses to erythrocyte (RBC)-bound antigens in the (CBA/N x B10)F1 mouse. Male B cells, which express the CBA/N defect, were shown to be unresponsive to RBC antigens when the delivered T cell helper activity was solely nonspecific. Thus we demonstrated that defective B cells did not respond to concanavalin A supernatants or bystander helper activity, in spite of the fact that CBA/N-defective mice could produce these T cell activities. The defective B cell did not respond to RBC-bound antigen in the presence of RBC-primed T cells, although the magnitude of this response was usually twofold less than normal controls. The insensitivity of CBA/N defective B cells to nonspecific T cell helper activities seemed to involve at least the inability of RBC antigens to activate defective B cells in the absence of antigen-specific T cell help.

Animals↗
PubMed1976

Functional heterogeneity among the T-derived lymphocytes of the mouse. V. Response kinetics of peripheral T cell subpopulations.

The kinetics of the proliferative response and the appearance of effectors of helper activity after stimulation by antigen were examined in T cell subpopulations. As defined in previous papers of this series, one population, T1, is short-lived after adult thymectomy (ATx), and relatively resistant to elimination by anti-thymocyte serum (ATS). Another population, T2, is long-lived after ATx, but highly sensitive to elimination by small doses of ATS. From precursors within the T2 population, effectors of specific helper activity, after priming with antigen, appeared within 1 to 2 days and reached a maximum on day 4. The responding cells reached their peak proliferative response within 24 hr after stimulation by antigen. In contrast, helper activity arising from T1 precursors first appeared on day 3 and peaked on day 5. These cells did not reach their maximal proliferative response until 60 hr after priming. These findings indicate additional useful markers for distinguishing the T1 and T2 subpopulations and are consistent with models for T cell development in which T1 cells are virgin cells and T2 cells are memory cells.

Animals↗
PubMed1976

Functional heterongeneity among the T-derived lymphocytes of the mouse. VI. Memory T cells stored in the T2 subpopulation.

Memory T cells were demonstrated in mice which were the precursors for cells causing sheep red blood cell-(SRBC) specific helper activity in the in vitro response of spleen cells to trinitrophenyl (TNP)-SRBC. These memory cells were distinguished from the effectors of helper activity generated during the primary response and were shown to belong to the T2 subpopulation of peripheral T cells on the basis of 1) their rapid response to a challenge with SRBC, 2) their long lifetime, and 3) their sensitivity to small in vivo doses of anti-thymocyte serum.

Animals↗
PubMed1975

Functional heterogeneity among the T-derived lymphocytes of the mouse. II. Sensitivity of subpopulations to anti-thymocyte serum.

A number of T cell functions were examined in mice after treatment with rabbit anti-mouse thymocyte serum (ATS). Two populations of T cells were distinguished; the first, sensitive, and a second, resistant, to elimination by ATS. The helper cell involved in the primary humoral response to sheep red blood cells (SRBC) was found within the sensitive population, whereas the T-cells required for the priming of mice with SRBC for helper activity or delayed hypersensitivity were found within both populations. Previous work and experiments utilizing both adult thymectomy and ATS treatment indicated that the ATS-sensitive population is long-lived, whereas the ATS-resistant population is short-lived.

Animals↗
PubMed1975

Antigen-specific and nonspecific mediators of T cell/B cell cooperation. I. Evidence for their production by different T cells.

Evidence is presented for two types of helper T cells in the mouse specific for a protein antigen, keyhole limpet hemocyanin (KLH). The first cell is able to help B cells respond to the hapten, trinitrophenyl (TNP), when coupled to KLH presumably through the participation of KLH-specific T cell factors. The second helper cell when stimulated with KLH is able to help B cells respond to red blood cell antigens, but not TNP-KLH, through the production of a non-antigen-specific factor. Both types of helper cells were shown to be present in the spleens of KLH-primed mice, although they occurred with different frequencies. They were shown to be different T cells by their segregation from each other in vitro at limiting dilution.

Animals↗
PubMed1975

Functional heterogeneity among the T-derived lymphocytes of the mouse. IV. Nature of spontaneously induced suppressor cells.

When spleen cells are cultured for 4 days in the presence of fetal bovine serum, T-cells are generated which nonspecifically suppress the humoral responses of non-precultured cells to a variety of antigens. These T cells can be generated from both short-lived, sessile T1 cells and long-lived, recirculating T2 cells, and thus appear similar to suppressor T cells activated by concanavalin A.

Animals↗