scholarly journals Spleen cells from adult mice given total lymphoid irradiation or from newborn mice have similar regulatory effects in the mixed leukocyte reaction. I. Generation of antigen-specific suppressor cells in the mixed leukocyte reaction after the addition of spleen cells from adult mice given total lymphoid irradiation.

1982 ◽  
Vol 156 (2) ◽  
pp. 522-538 ◽  
Author(s):  
S Okada ◽  
S Strober
Keyword(s):  
Suppressor Cells ◽  
Allogeneic Bone ◽  
Mixed Leukocyte Reaction ◽  
Spleen Cells ◽  
Newborn Mice ◽  
Total Lymphoid Irradiation ◽  
Adult Mice ◽  
Regulatory Effects

We added spleen cells from adult BALB/c mice treated with total lymphoid irradiation (TLI) to the mixed leukocyte reaction (MLR) using a variety of responder and stimulator cells. The spleen cells nonspecifically suppressed the uptake of [3H]-thymidine and the generation of cytolytic cells regardless of the responder-stimulator combination used. We also examined the effect of the spleen cells on the generation of antigen-nonspecific and antigen-specific suppressor cells in the MLR. The experimental results suggest that the spleen cells from TLI-treated mice inhibit the generation of nonspecific suppressor cells, but do not inhibit the generation of antigen-specific suppressor cells. Thus, alloantigenic stimulation of normal responder cells in vitro in the presence of spleen cells from TLI-treated mice generates large numbers of antigen-specific suppressor cells, but few cytolytic cells or nonspecific suppressor cells. Similar nonspecific inhibition of the MLR was observed with neonatal spleen cells. This in vitro system provides a regulatory model for the induction and maintenance of tolerance in vivo, in which adult mice given TLI or neonatal mice accept allogeneic bone marrow transplants without graft-vs.-host disease.

scholarly journals Mechanisms of idiotype suppression. I. In vitro generation of idiotype-specific suppressor T cells by anti-idiotype antibodies and specific antigen.

1979 ◽  
Vol 149 (6) ◽  
pp. 1371-1378 ◽  
Author(s):  
B S Kim
Keyword(s):  
T Cells ◽  
Specific Antigen ◽  
Suppressor Cells ◽  
Culture Period ◽  
Spleen Cells ◽  
Suppressor T Cells ◽  
Myeloma Protein ◽  
Specific Suppressor T Cells

Normal BALB/c spleen cells are unresponsive in vitro to the phosphorylcholine (PC) determinant in the presence of anti-idiotype antibodies specific for the TEPC-15 myeloma protein (T15) which carries an idiotypic determinant indistinguishable from that of most anti-PC antibodies in BALB/c mice. The possibility that idiotype-specific suppressor cells may be generated during the culture period was examined by coculturing the cells with untreated syngeneic spleen cells. Cells that had been preincubated with anti-T15 idiotype (anti-T15id) antibodies and a PC-containing antigen, R36a for 3 d, were capable of specifically suppressing the anti-PC response of fresh normal spleen cells, indicating that idiotype-specific suppressor cells were generated during the culture period. The presence of specific antigen also appeared to be necessary because anti-T15id antibodies and a control antigen, DNP-Lys-Ficoll, were not capable of generating such suppressor cells. Suppressor cells were induced only in the population of spleen cells nonadherent to nylon wool and the suppressive activity was abrogated by treatment with anti-Thy 1.2 serum and complement. These results indicate that anti-idiotype antibodies and specific antigen can generate idiotype-specific suppressor T cells in vitro. These in vitro results may reflect in vivo mechanisms of idiotype suppression.

scholarly journals GENETIC CONTROL OF IMMUNE RESPONSES IN VITRO

1974 ◽  
Vol 140 (3) ◽  
pp. 648-659 ◽  
Author(s):  
Judith A. Kapp ◽  
Carl W. Pierce ◽  
Stuart Schlossman ◽  
Baruj Benacerraf
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Cell Function ◽  
Suppressor Cells ◽  
Specific Response ◽  
Spleen Cells ◽  
X Irradiation

In recent studies we have found that GAT not only fails to elicit a GAT-specific response in nonresponder mice but also specifically decreases the ability of nonresponder mice to develop a GAT-specific PFC response to a subsequent challenge with GAT bound to the immunogenic carrier, MBSA. Studies presented in this paper demonstrate that B cells from nonresponder, DBA/1 mice rendered unresponsive by GAT in vivo can respond in vitro to GAT-MBSA if exogenous, carrier-primed T cells are added to the cultures. The unresponsiveness was shown to be the result of impaired carrier-specific helper T-cell function in the spleen cells of GAT-primed mice. Spleen cells from GAT-primed mice specifically suppressed the GAT-specific PFC response of spleen cells from normal DBA/1 mice incubated with GAT-MBSA. This suppression was prevented by pretreatment of GAT-primed spleen cells with anti-θ serum plus C or X irradiation. Identification of the suppressor cells as T cells was confirmed by the demonstration that suppressor cells were confined to the fraction of the column-purified lymphocytes which contained θ-positive cells and a few non-Ig-bearing cells. The significance of these data to our understanding of Ir-gene regulation of the immune response is discussed.

scholarly journals Suppressor T cells activated in a primary in vitro response to non-major histocompatibility alloantigens.

1982 ◽  
Vol 156 (5) ◽  
pp. 1398-1414 ◽  
Author(s):  
S Macphail ◽  
O Stutman
Keyword(s):  
Mixed Lymphocyte Reaction ◽  
Cytotoxic T Lymphocyte ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Spleen Cells ◽  
Suppressor T Cells ◽  
Normal Spleen ◽  
In Vitro Response

Normal mouse spleen cells are not capable of mounting a primary cytotoxic T lymphocyte (Tc) response to non-H-2 alloantigens in vitro, although a good secondary H-2-restricted response is observable after in vivo immunization of the responder animals. Suppressor cells are generated in such a primary responses provided a Mls incompatibility exists between the responder and stimulator. These suppressors are not antigen specific, are Thy-1+, Lyt-1+, 2-, I-J-, and are highly radiosensitive. The suppressor cell precursors in normal spleen express the same phenotype. These suppressor cells are probably implicated in the lack of a primary Tc response in a primary mixed lymphocyte reaction across non-H-2 incompatibilities that include an Mls difference.

scholarly journals Suppressor cells: dependence on assay conditions for functional activity.

1976 ◽  
Vol 143 (5) ◽  
pp. 1211-1219 ◽  
Author(s):  
D D Eardley ◽  
M O Staskawicz ◽  
R K Gershon
Keyword(s):  
T Cells ◽  
Antibody Response ◽  
Functional Activity ◽  
Blood Cells ◽  
Suppressor Cells ◽  
Target Population ◽  
Spleen Cells ◽  
Regulatory Effects ◽  
Assay Conditions

Spleen cells educated in vitro with sheep red blood cells (SRBC) suppressed the plaque-forming cell response of Mishell-Dutton assay cultures challenged with optimal doses of SRBC. Changing conditions in the assay cultures changed the effect educated cells had on the assay culture responses. For example, educated cells helped rather than suppressed assay cultures of suboptimal numbers of spleen cells. Similarly, augmentation resulted upon addition of educated cells to assay cultures challenged with suboptimal doses of SRBC. Such a reversal of regulatory effects was not observed when assay cultures were challenged with supraoptimal antigen doses. Educated cells helped assay cultures of B spleen cells, and the addition of normal T cells reinstated suppression. Furthermore, maintenance of assay cultures under stationary rather than the usual rocking conditions allowed educated cells to help rather than suppress the antibody response of assay cultures. These results show that when the response of the target population (assay cultures) is low, the regulator (educated) cells augment the response, and vice versa, supporting the hypothesis that the effect regulator cells produce depends on the activity of the cells they regulate.

scholarly journals Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VII. Idiotype-specific suppression of plaque-forming cell responses.

1981 ◽  
Vol 153 (3) ◽  
pp. 640-652 ◽  
Author(s):  
D H Sherr ◽  
S T Ju ◽  
J Z Weinberger ◽  
B Benacerraf ◽  
M E Dorf
Keyword(s):  
B Cells ◽  
Suppressor Cells ◽  
Spleen Cells ◽  
In Vitro System ◽  
Specific Suppression ◽  
Cell Responses ◽  
T Suppressor Cells

The ability of suppressor cells induced by the intravenous administration of 4-hydro-3-nitrophenyl acetyl (NP)-modified syngeneic cells to reduce an idiotypic B cell response was studied in both an in vivo and an in vitro system. Idiotype-positive B cells were assayed by the ability of guinea pig anti-idiotypic antiserum to specifically inhibit idiotype-positive plaque formation. It was found that up to 57% of the PFC response in vivo and 100% of the PFC response in vitro was inhibitable with antiidiotypic antiserum. The expression of these idiotype-positive B cells could be suppressed by the transfer of spleen cells form mice treated 7 d previously with NP coupled syngeneic cels. T cells are both required and sufficient for the transfer of idiotype specific suppression. The induction of these idiotype-specific T suppressor cells directly with antigen suggests that recognition of unique determinants on cell surfaces is important for regulation of lymphoid cell interactions. The role of idiotype-specific suppressor cells in the network of lymphoid interactions is discussed.

scholarly journals Rearrangement and expression of T cell receptor genes in cloned murine natural suppressor cell lines

1987 ◽  
Vol 166 (4) ◽  
pp. 1168-1173 ◽  
Author(s):  
B Hertel-Wulff ◽  
T Lindsten ◽  
R Schwadron ◽  
DM Gilbert ◽  
MM Davis ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Chain Gene ◽  
Total Lymphoid Irradiation ◽  
Adult Mice ◽  
Graft Vs Host Disease ◽  
Β Chain

Naturally occurring suppressor cells of the in vitro mixed leukocyte culture reaction and of in vivo graft-vs.-host disease have been identified in the spleens of neonatal mice (1) and of adult mice recovering from total lymphoid irradiation (2), whole-body irradiation (3), and syngeneic marrow transplantation (4), or cyclophosphamide therapy (5). Using both positive and negative selection procedures, the suppressors were reported to be null lymphocytes that did not express mature macrophage surface markers, nor differentiate into mature macrophages in vitro, nor demonstrate natural killer (NK) activity (1). Subsequently, cloned lines of these natural suppressor (NS) cells were derived from either adult mice given total lymphoid irradiation (TLI) (2) or from neonates (6). The cloned NS cell lines expressed a surface phenotype (2, 6) similar to that reported previously for cloned NK cells (Thy-1(+), asialo-GM1(+), Ig(-), Lyt-1(-), Lyt-2(-), Ia(-), MAC-1(-)) (7-9). However, the NS cells did not show NK activity in the standard assay with YAC-1 target cells. The cloned NS lines suppressed the proliferation of responder cells and the generation of cytolytic cells in the mixed leukocyte reaction (MLR), and suppressed lethal graft-vs.-host disease in vivo (10, 11). In view of the unusual function and surface phenotype of the cells, the lineage of these cells remained unclear. To determine the lineage of the cloned NS cells, we searched for expression and rearrangement of the α and β chain genes of the T cell antigen receptor, as well as that of the γ chain gene. Studies of the phenotypically similar NK cell yielded conflicting results. Thus, cloned lines of murine NK cells were reported to have rearrangements of the β chain genes, and to express mRNA for all three chains (12). In contrast, freshly purified rat or human large granular lymphocytes (LGL) were shown to express only the 1.0 kb mRNA species of the β chain gene (13), indicative of D-J joining (14). Thus, some but not all cells with NK function express the T cell receptor and are members of the T cell lineage. The current report shows that the NS lines express full-length mRNA transcripts for the a and β chain of the T cell receptor, as well as the γ chain gene.

scholarly journals Involvement of Hdac3-mediated inhibition of microRNA cluster 17-92 in bronchopulmonary dysplasia development

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Di Wang ◽  
Hui Hong ◽  
Xiao-Xia Li ◽  
Jing Li ◽  
Zhi-Qun Zhang
Keyword(s):  
Bronchopulmonary Dysplasia ◽  
Promoter Region ◽  
Placental Growth Factor ◽  
Lung Fibroblasts ◽  
Newborn Mice ◽  
Histone Deacetylase 3 ◽  
Adult Mice ◽  
Medical Advances

Abstract Background The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances. Histone deacetylase 3 (Hdac3) has been reported to be a crucial regulator in alveologenesis. Hence, this study aims to investigate the mechanism of Hdac3 in the abnormal pulmonary angiogenesis and alveolarization of BPD. Methods A hyperoxia-induced BPD model of was developed in newborn mice, and primary lung fibroblasts were isolated from adult mice. Hdac3 was knocked out in vivo and knocked down in vitro, while microRNA (miR)-17 was downregulated in vivo and in vitro to clarify their roles in abnormal pulmonary angiogenesis and alveolarization. Mechanistic investigations were performed on the interplay of Hdac3, miR-17-92 cluster, enhancer of zeste homolog 1 (EZH1), p65 and placental growth factor (Pgf). Results Hdac3 was involved in abnormal alveolarization and angiogenesis in BPD mice. Further, the expression of the miR-17-92 cluster in BPD mice was downregulated by Hdac3. miR-17 was found to target EZH1, and Hdac3 rescued the inhibited EZH1 expression by miR-17 in lung fibroblasts. Additionally, EZH1 augmented Pgf expression by recruiting p65 thus enhancing the progression of BPD. Hdac3 augmented the recruitment of p65 in the Pgf promoter region through the miR-17/EZH1 axis, thus enhancing the transcription and expression of Pgf, which elicited abnormal angiogenesis and alveolarization of BPD mice. Conclusions Altogether, the present study revealed that Hdac3 activated the EZH1-p65-Pgf axis through inhibiting miR-17 in the miR-17-92 cluster, leading to accelerated abnormal pulmonary angiogenesis and alveolarization of BPD mice.

scholarly journals Effect of recent antigen priming on adoptive immune responses. III. Antigen-induced selective recruitment of subsets of recirculating lymphocytes reactive to H-2 determinants.

1976 ◽  
Vol 143 (3) ◽  
pp. 585-600 ◽  
Author(s):  
J Sprent ◽  
J F Miller
Keyword(s):  
Parental Strain ◽  
Suppressor Cells ◽  
Third Party ◽  
Spleen Cells ◽  
Skin Allograft ◽  
Produce Cell ◽  
F1 Hybrid ◽  
Activated State

Information was sought on the reactivity of thoracic duct lymphocytes (TDL) from parental strain mice injected intravenously with large numbers of irradiated semiallogeneic spleen cells. TDL collected at 1 day after spleen cell injection were almost totally depleted of lymphocytes able to produce cell-mediated lympholysis (CML), a graft-versus-host (GVH) reaction, and skin allograft rejection against the H-2 determinants on the injected spleen cells. Normal or near normal responses were observed against third-party determinants. In the case of CML, there was no evidence that the unresponsiveness was due to suppressor cells. In marked contrast, the capacity of TDL to exert a specific mixed lymphocyte reaction (MLR) against the injected determinants was reduced by no more than two to fourfold; this applied whether MLR were measured in vivo or in vitro. Injection of normal rather than irradiated semiallogeneic spleen cells gave similar results. Complete and specific removal of MLR-producing lymphocytes was achieved, however, in a different system in which parental strain T cells were filtered from blood to lymph through irradiated F1 hybrid mice. Since this system presumably provided a much higher concentration of H-2 determinants to the responding lymphocytes, it is suggested that the differing results obtained with these two systems may indicate that certain cells reactive to H-2 determinants are of low affinity, their reactivity being detected in the MLR, but not by other parameters. With both systems, MLR-producing lymphocytes reappeared in the lymph after 2-3 days; the cells collected at this stage gave an MLR of altered kinetics. The present data, in toto, suggest that under certain conditions of antigen presentation, virtually all recirculating lymphocytes reactive to a given set of H-2 determinants can be induced to leave the circulation for a period of 1-2 days. After responding to the injected determinants (presumably in organs such as the spleen), the cells re-enter the circulation in an activated state after 2-3 days.

Inhibition of T Cell Alloreactivity by Gr-1+Mac-1+ Myeloid Suppressor Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5177-5177
Author(s):  
Xiao Chen ◽  
Jon Anderson ◽  
William R. Drobyski
Keyword(s):  
T Cell ◽  
Adoptive Transfer ◽  
Fluorescent Protein ◽  
Suppressor Cells ◽  
Major Complication ◽  
Spleen Cells ◽  
Regulatory Cell ◽  
Myeloid Suppressor Cells

Abstract Graft-versus-host-disease (GVHD) remains the major complication of allogeneic stem cell transplantation (SCT). While pharmacological approaches have long been the mainstay of GVHD prevention, recent strategies have focused on cellular approaches, specifically the use of regulatory cell populations to prevent or mitigate the severity of GVHD. Gr-1+Mac-1+ myeloid-derived cells, termed myeloid suppressor cells (MSCs), are a regulatory cell population that has been shown to play an important role in the suppression of tumor and anti-infectious immunity. In these studies, we examined whether these cells were detectable in GVHD recipients and played any role in the suppression of alloreactive T cell responses in vitro and in vivo. Lethally irradiated Balb/c (H-2d) mice were transplanted with MHC-incompatible C57BL/6 (H-2b) bone marrow and spleen cells to induce GVHD. Immature myeloid cells with a Gr-1+Mac-1+ phenotype were found to constitute 60% of all splenocytes at day 10 post-SCT thereafter declining to 30% by day 21. MSCs isolated from the spleens of mice with GVHD expressed high levels of class I and II, but low levels of the costimulatory molecules CD80, CD86, CD40 and were negative for CD11c. Highly purified Gr-1+ Mac-1+ cells obtained from the spleens of GVHD mice 10 or 21 days post-SCT potently suppressed naive T cell proliferation in a standard MLC by 70% at a responder to suppressor ratio of 1:1. Notably, MSCs could also be generated in vitro from normal B6 BM after 6 days in culture with G-CSF and were equally potent at suppressing T cell alloreactivity. Suppression was partially mediated by nitric oxide (NO) as addition of the NO inhibitor L-NMA reversed 50% of the inhibitory effect. To determine whether MSCs exerted a suppressive effect in vivo, lethally irradiated Balb mice were transplanted with B6 BM plus naïve spleen cells with or without MSCs obtained from the spleens of GVHD animals 10 or 21 days post-BMT. The adoptive transfer of MSCs failed to protect mice from GVHD when assessed by overall survival, serial weight measurements or histological analysis. As an alternative approach to augment GVHD protection, G-CSF was administered for 14 days beginning at the time of BMT to enhance the in vivo survival of MSCs. G-CSF administration in both irradiated and non-irradiated MHC-incompatible GVHD mouse models, however, also had no protective effect. We reasoned that a possible explanation for the lack of an effect in vivo was that MSCs did not appropriately localize to nodal sites where GVHD is initiated. To examine this question, B6-green fluorescent protein (GFP) mice were used as donor animals to permit the detection and trafficking of MSCs in vivo. Adoptive transfer of B6 GFP-MSCs from the spleens of GVHD mice 10 days after SCT demonstrated that these cells could be detected in the secondary lymphoid organs of recipient mice 20 hours after BMT, but were completely absent by day 3, supporting the premise that the lack of protection was attributable, at least in part, to the inability of these cells to persist at nodal sites where T cell priming against host alloantigens was occurring. These results indicate that MSCs, which are present in the spleen of GVHD recipients, show potent T cell suppressive capacity in vitro, but fail to mediate a similar effect in vivo. Lack of protection appears to be due to the inability of these cells to localize to all critical secondary lymphoid sites underscoring the importance that the capability of regulatory cells to migrate to and persist at appropriate tissue sites plays in the design of cellular strategies to prevent GVHD.

scholarly journals Mechanisms of genetic resistance to Friend virus leukemia. III. Susceptibility of mitogen-responsive lymphocytes mediated by T cells.

1976 ◽  
Vol 143 (4) ◽  
pp. 728-740 ◽  
Author(s):  
V Kumar ◽  
T Caruso ◽  
M Bennett
Keyword(s):  
T Cells ◽  
B Cell ◽  
Genetic Resistance ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
M Cells ◽  
Spleen Cells ◽  
T Suppressor Cells

Friend leukemia virus (FV) suppressed the proliferative responses of spleen, lymph node, marrow, and thymus cell populations to various T- and B-cell mitogens. Cells taken from mice, e.g. BALB/c genetically susceptible to leukemogenesis in vivo were much more susceptible to suppression of mitogenesis in vitro than similar cells from genetically resistant mice, e.g., C57BL/6. Nylon wool-purified splenic T cells from BALB/c and C3H mice lost susceptibility to FV-induced suppression of mitogenesis but became suppressible by addition of 10% unfiltered spleen cell. Thus, FV mediates in vitro suppression of lymphocyte proliferation indirectly by "activating" a suppressor cell. The suppressor cell adhered to nylon wool but not to glass wool or rayon wool columns. Pretreatment of spleen cells with carbonyl iron and a magnet did not abrogate the suppressor cell function. Suppressor cells were not eliminated by treatment with rabbit antimouse immunoglobulin (7S) and complement (C). However, high concentrations of anti-Thy-1 plus C destroyed suppressor cells of the spleen; thymic suppressor cells were much more susceptible to anti-Thy-1 serum. Nude athymic mice were devoid of suppressor cells and their B-cell proliferation was relatively resistant to FV-induced suppression in vitro. The suppressor cells in the thymus (but not in the spleen) were eliminated by treatment of mice with cortisol. Thus, FV appears to mediate its suppressive effect on mitogen-responsive lymphocytes by affecting "T-suppressor cells." Spleen cells from C57BL/6 mice treated with 89Sr to destroy marrow-dependent (M) cells were much more suppressible by FV in virto than normal C57BL/6 spleen cells. However, nylon-filtered spleen cells of 89Sr-treated C57BL/6 mice were resistant to FV-induced suppression in vitro, indicating that the susceptibility of spleen cells from 89Sr-treated B6 mice is also mediated by suppressor cells. Normal B6 splenic T cells were rendered susceptible to FV-induced suppression of mitogenesis by addition of 10% spleen cells from 89Sr-treated B6 mice. Thus, M cells appear to regulate the numbers and/or functions of T-suppressor cells which in turn mediate the immunosuppressive effects of FV in vitro. Neither mitogen-responsive lymphocytes nor T-suppressor cells are genetically resistant or susceptible to FV. The genetic resistance to FV is apparently a function of M cells, both in vitro as well as in vivo.

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