scholarly journals I-J-restricted interactions in the generation of azobenzenearsonate-specific suppressor T cells.

1982 ◽  
Vol 156 (5) ◽  
pp. 1325-1334 ◽  
Author(s):  
M Takaoki ◽  
M S Sy ◽  
A Tominaga ◽  
A Lowy ◽  
M Tsurufuji ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antigen Presentation ◽  
Cytotoxic T Lymphocyte ◽  
Suppressor Cells ◽  
Delayed Type Hypersensitivity ◽  
Third Order ◽  
Different Types ◽  
Coupled Cells ◽  
Different Strains ◽  
Specific Suppressor T Cells

The genetic restrictions of the activation of third-order suppressor cells (Ts3) were studied in mice, using two different types of anti-azobenzenearsonate (ABA)-immune responses, namely delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) generation. Ts2 cells were induced in several different strains of mice by injecting monoclonal T hybridoma molecules or first-order suppressor factors (TsF1) originating in A/J (H-2a, Igh-1e) mice and then testing the TsF2 molecules derived from these Ts2 in A/J and A.By (H-2b, Igh-1e) or (A/J X A.By)F1 (H-2a/b, Igh-1e) and (C57Bl/6 X A/J)F1 (H-2b/a, Igh-1e) mice. It was shown that the activity of TsF2 was restricted to the I-J of the strain in which Ts2 was induced. By genetic analysis, restriction was shown to be due to the requirement of H-2 identity between ABA-coupled cells used for Ts3 activation and the strain of the TsF2 origin. Moreover, by using H-2-congenic ABA-coupled cells, we were also able to precisely map and demonstrate that ABA-coupled cells I-J identical to TsF2 induced in various strains were necessary for effective suppression to occur. This selective activation of Ts3 suggested the existence of I-J-related antigen presentation for suppression as the counterpart of I-A or I-A-I-E-restricted antigen presentation for positive immune responses.

scholarly journals Mechanism responsible for the induction of I-J restriction on TS3 suppressor cells.

1982 ◽  
Vol 156 (5) ◽  
pp. 1502-1515 ◽  
Author(s):  
M Minami ◽  
N Honji ◽  
M E Dorf
Keyword(s):  
Antigen Presentation ◽  
Suppressor Cells ◽  
General Mechanism ◽  
T Helper ◽  
Suppressor T Cells ◽  
Third Order ◽  
Splenic Cell ◽  
Parental Haplotype ◽  
Coupled Cells ◽  
Subsequent Activation

The mechanisms responsible for the induction of I-J restrictions on third-order suppressor T cells (TS3) were analyzed. The I-J phenotype of the antigen-coupled cells used for priming restricted the specificity of the TS3 population. Thus, TS3 cells were only generated after priming with antigen-coupled I-J homologous cells. Identity at the I-JM (and I-E) subregions was sufficient for TS3 induction. Furthermore, priming of H-2 heterozygous mice with antigen-coupled parental cells generated TS3 that were restricted to the parental haplotype used for priming. The splenic cell population responsible for antigen presentation and induction of TS3 cells was fractionated. The cells involved in antigen presentation were found in the splenic adherent population and were absent in the fraction containing splenic nonadherent T and B cells. The subsequent activation and interaction of TS3 cells is also restricted by genes in the H-2 complex. The results are discussed in terms of a general mechanism responsible for the induction of restrictions in T helper and TS3 cells.

scholarly journals Antigen- and receptor-driven regulatory mechanisms. II. Induction of suppressor T cells with idiotype-coupled syngeneic spleen cells.

1979 ◽  
Vol 150 (5) ◽  
pp. 1229-1240 ◽  
Author(s):  
M S Sy ◽  
B A Bach ◽  
A Brown ◽  
A Nisonoff ◽  
B Benacerraf ◽  
...  
Keyword(s):  
T Cells ◽  
Heavy Chain ◽  
Suppressor Cells ◽  
Significant Inhibition ◽  
Regulatory Mechanisms ◽  
Delayed Type Hypersensitivity ◽  
Spleen Cells ◽  
Suppressor T Cells ◽  
Specific Manner ◽  
Coupled Cells

Anti-p-azobenzenearsonate (ABA) antibodies, coupled covalently to normal syngeneic spleen cells and then given intravenously to normal animals, were found to be potent tolerogens for delayed-type hypersensitivity (DTH) to ABA. The ability of the antibody-coupled cells to induce tolerance was determined to be a result of the cross-reactive idiotype (CRI+) fraction of the antibodies, because anti-ABA antibodies lacking the CRI+ components when coupled to spleen cells were unable to cause any significant inhibition. Furthermore, genetic analysis revealed that the ability of CRI-coupled cells to inhibit ABA-specific DTH is linked to Igh-1 heavy chain allotype, in as much animals which possess heavy chain allotypes similar to that of A/J were sensitive to this inhibition. Adoptive transfer experiments provided evidence that CRI-coupled cells induce suppressor cells, and spleen cells or thymocytes from animals received CRI-coupled cells were able to transfer suppression to naive recipients. In addition, treatment with anti-Thy1.2 serum plus complement completely abrogated their ability to transfer suppression. Thus, this active suppression is a T-cell-dependent phenomenon. In investigating the specificity of these suppressor T cells, it was found that they functioned in an antigen-specific manner and were unable to suppress the development of DTH to an unrelated hapten 2,4-dinitro-1-fluorobenzene.

scholarly journals Antigen- and receptor-driven regulatory mechanisms. VIII. Suppression of idiotype-negative, p-azobenzenearsonate-specific T cells results from the interaction of an anti-idiotypic second-order T suppressor cell with a cross-reactive-idiotype-positive, p-azobenzenearsonate-primed T cell target.

1981 ◽  
Vol 153 (6) ◽  
pp. 1415-1425 ◽  
Author(s):  
M S Sy ◽  
A Nisonoff ◽  
R N Germain ◽  
B Benacerraf ◽  
M I Greene
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Second Order ◽  
T Cell Response ◽  
Delayed Type Hypersensitivity ◽  
Coupled Cells

The suppressor pathway that regulates the T cell response to p-azobenzenearsonate (ABA)-coupled cells has been studied. It has been found that the ability of anti-idiotypic second-order T suppressor cells (Ts2) to inhibit T cell-dependent delayed-type hypersensitivity (DTH) responses depended upon the presence of cross-reactive-idiotype (CRI)-bearing T cells present in ABA-primed mice. This suppressor T cell subset, termed Ts2, so exists with CRI-negative T cells that mediate DTH in vivo. It appears that antigen-activated CRI+ Ts3 require signals from the anti-CRI Ts2 subset to suppress DTH reactions in an idiotype-nonspecific manner. The relevance of these observations to a comprehensive scheme of T and B cell regulation is discussed.

scholarly journals Antigen- and receptor-driven regulatory mechanisms. I. Induction of suppressor T cells with anti-idiotypic antibodies.

1979 ◽  
Vol 150 (5) ◽  
pp. 1216-1228 ◽  
Author(s):  
M S Sy ◽  
B A Bach ◽  
Y Dohi ◽  
A Nisonoff ◽  
B Benacerraf ◽  
...  
Keyword(s):  
T Cells ◽  
Suppressor Cells ◽  
Regulatory Mechanisms ◽  
Delayed Type Hypersensitivity ◽  
Low Doses ◽  
Spleen Cells ◽  
Suppressor T Cells ◽  
Humoral Antibodies ◽  
Coupled Cells ◽  
Immunoglobulin Molecule

Delayed-type hypersensitivity (DTH) to the azobenzenearsonate (ABA) hapten can be readily induced in A/J mice injecting ABA-coupled syngeneic spleen cells subcutaneously. To further characterize this T-cell-dependent immunological phenomenon, the effect of passively administered anti-cross-reactive idiotype common to anti-ABA antibodies of A/J mice (CRI) antibodies on the development of ABA-specific DTH was investigated. Animals given daily injections (of minute amounts) of anti-CRI antibodies subsequent to immunization with ABA-coupled cells show significant reduction of ABA specific responses. This inhibition is antigen specific and requires the intact immunoglobulin molecule, as F(ab')2 treatments were ineffective in suppressing the reaction. Investigations of the mechanism of the anti-CRI-induced suppression of ABA DTH revealed that the observed suppression is a result of the activation of suppressor cells. Spleen cells taken from animals which received anti-CRI antibodies were able to adoptively transfer suppression to naive recipients. This suppression was shown to be mediated by T cells, as anti-Thy1.2 plus complement completely abrogated the transfer of suppression. In addition, animals pretreated with low doses of cyclophosphamide were not suppressed by the administration of anti-CRI antibodies. The genetic restriction of anti-CRI-induced suppression was demonstrated. Antibodies to the major cross-reactive idiotype, (CRI) associated with anti-ABA antibodies in A/J mice were unable to suppress the development of DTH to ABA in BALB/c mice (H-2d, Igh-1a). Such antibodies were, however, fully active in suppressing ABA DTH in the allotype-congenic C.AL-20 strain which has an allotype (Igh-1d) similar to that of A/J (Igh-1e) on a BALB/c background, and which produces humoral antibodies with the CRI.

Peripheral blood lymphocytes genetically modified to express the self/tumor antigen MAGE-A3 induce antitumor immune responses in cancer patients

Blood ◽  
2009 ◽  
Vol 113 (8) ◽  
pp. 1651-1660 ◽  
Author(s):  
Raffaella Fontana ◽  
Marco Bregni ◽  
Arcadi Cipponi ◽  
Laura Raccosta ◽  
Cristina Rainelli ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Tumor Antigen ◽  
Cytotoxic T Lymphocyte ◽  
Genetically Modified ◽  
Peripheral Blood Lymphocytes ◽  
The Self ◽  
Delayed Type Hypersensitivity ◽  
Melanoma Patients

Abstract Dendritic cell (DC) targeting in vivo has recently been shown to confer strong and protective cytotoxic T lymphocyte (CTL)–based immunity in tumor murine models. Our group has recently demonstrated in preclinical models that the infusion of genetically modified lymphocytes (GMLs) expressing the self/tumor antigen TRP-2 is able to elicit functional TRP-2–specific effectors with antitumor activity by targeting DCs in vivo. Here we have analyzed vaccine- and tumor-specific immune responses of 10 melanoma patients treated with autologous GMLs expressing the cancer germline gene MAGE-A3. Three of 10 patients treated with MAGE-A3–GML showed an increase of circulating anti–MAGE-A3 T cells, and developed skin delayed-type hypersensitivity to MAGE-A3. Interestingly, in 2 of these patients, with progressive and measurable tumors at study entry, anti–MAGE-A3 T cells were detected not only in the blood but also within tumors resected after vaccination. These results demonstrate that the infusion of MAGE-A3–GML elicits antitumor T cells, which are capable of trafficking to inflamed tissues and of infiltrating tumors. Clinical studies on a larger group of patients are needed to evaluate the clinical efficacy of such a strategy.

scholarly journals Analysis of T cell hybridomas. III. Distinctions between two types of hapten-specific suppressor factors that affect plaque-forming cell responses.

1983 ◽  
Vol 157 (2) ◽  
pp. 515-529 ◽  
Author(s):  
D H Sherr ◽  
M Minami ◽  
K Okuda ◽  
M E Dorf
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Suppressor Cells ◽  
Third Order ◽  
Cell Responses ◽  
Collective Data ◽  
Effector Phase ◽  
Mild Reduction

The ability of two cloned T cell hybridomas and their products to specifically suppress the in vitro plaque-forming cell (PFC) response to the 4-hydroxy-3-nitrophenyl acetyl hapten (NP) was studied. Supernatant from one hybridoma (TS1) was shown to suppress in the induction but not the effector phase of the immune response. Supernatant from the TS1 hybridoma was capable of inducing second-order (TS2) effector-phase suppressor cells in vitro but did not suppress the response of anti-I-J plus C-treated responder cells. In contrast, supernatant from a second hybridoma (TS3) was capable of suppressing PFC responses when added either in the induction or the effector phase of the response. TS3 supernatant was unable to induce effector-phase suppressor cells but was capable of suppressing the response of anti-I-J plus C-treated responder cells. In addition, specific suppressor factors isolated from supernatants of the TS1 and TS3 hybridomas were shown to bind to NP, bear NPb idiotypic and I-J-encoded but not immunoglobulin-constant region determinants. The factor secreted by the TS3 hybridoma appears to act directly on B cell targets. Mild reduction of this factor results in two separable moieties, only one of which binds NP. Reconstitution experiments suggest that both chains are required for function. The collective data indicate that these hybridomas represent cells from first- and third-order suppressor T cell populations described previously in contact sensitivity and in vitro PFC systems. The implications of the ability of these hybridoma products to affect both T and B cell-mediated immune responses are discussed.

scholarly journals Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection

2020 ◽  
Vol 8 (12) ◽  
pp. 1995
Author(s):  
Yoku Hayakawa ◽  
Yoshihiro Hirata ◽  
Masahiro Hata ◽  
Mayo Tsuboi ◽  
Yukiko Oya ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Immune Responses ◽  
Cell Fate ◽  
Knockout Mice ◽  
Suppressor Cells ◽  
Inflammatory Cells ◽  
Immune Disorder ◽  
Host Immune Responses ◽  
Epithelial Homeostasis ◽  
H Pylori

The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling.

scholarly journals Implementation of Adenovirus-Mediated Pulmonary Expression of Human ACE2 in HLA Transgenic Mice Enables Establishment of a COVID-19 Murine Model for Assessment of Immune Responses to SARS-CoV-2 Infection

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 940
Author(s):  
Theodor Chitlaru ◽  
Erez Bar-Haim ◽  
Liat Bar-On ◽  
Shahar Rotem ◽  
Hila Cohen ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Immune Responses ◽  
Post Infection ◽  
High Reproducibility ◽  
Cellular Immune Responses ◽  
Loss Of Weight ◽  
Transient Loss ◽  
Different Strains ◽  
Cellular Immune ◽  
Human Specific

HLA transgenic mice are instrumental for evaluation of human-specific immune responses to viral infection. Mice do not develop COVID-19 upon infection with SARS-CoV-2 due to the strict tropism of the virus to the human ACE2 receptor. The aim of the current study was the implementation of an adenovirus-mediated infection protocol for human ACE2 expression in HLA transgenic mice. Transient pulmonary expression of the human ACE2 receptor in these mice results in their sensitisation to SARS-CoV-2 infection, consequently providing a valuable animal model for COVID-19. Infection results in a transient loss in body weight starting 3 days post-infection, reaching 20–30% loss of weight at day 7 and full recovery at days 11–13 post-infection. The evolution of the disease revealed high reproducibility and very low variability among individual mice. The method was implemented in two different strains of HLA immunized mice. Infected animals developed strong protective humoral and cellular immune responses specific to the viral spike-protein, strictly depending on the adenovirus-mediated human ACE2 expression. Convalescent animals were protected against a subsequent re-infection with SARS-CoV-2, demonstrating that the model may be applied for assessment of efficacy of anti-viral immune responses.

scholarly journals Endogenous antigen presentation impacts on T-box transcription factor expression and functional maturation of CD8+ T cells

Blood ◽  
2012 ◽  
Vol 120 (16) ◽  
pp. 3237-3245 ◽  
Author(s):  
Corey Smith ◽  
Diah Elhassen ◽  
Stephanie Gras ◽  
Katherine K. Wynn ◽  
Vijayendra Dasari ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Antigen Presentation ◽  
Cd8 T Cells ◽  
Viral Antigen ◽  
Cytotoxic T Lymphocyte ◽  
Granzyme B ◽  
T Box ◽  
Differentiation Status ◽  
Human Cmv

Abstract T-box transcription factors T-bet (Tbx21) and Eomesodermin (Eomes) are critical players in CD8+ cytotoxic T lymphocyte effector function and differentiation, but how the expression of these transcription factors is regulated remains poorly defined. Here we show that dominant T cells directed toward human CMV, expressing significantly higher levels of T-bet with graded loss of Eomes expression (T-bethiEomeshi/lo), are more efficient in recognizing endogenously processed peptide-major histocompatibility complexes (pMHC) compared with subdominant virus-specific T cells expressing lower levels of T-bet and high levels of Eomes (T-betintEomeshi). Paradoxically, the T-bethiEomeshi/lo dominant populations that efficiently recognized endogenous antigen demonstrated lower intrinsic avidity for pMHC, whereas T-betintEomeshi subdominant populations were characterized by higher pMHC avidity and less efficient recognition of virus-infected cells. Importantly, differential endogenous viral antigen recognition by CMV-specific CD8+ T cells also correlated with the differentiation status and expression of perforin, granzyme B and K. Furthermore, we demonstrate that the expression of T-bet correlates with clonal expansion, differentiation status, and expression of perforin, granzyme B and K in antigen-specific T cells. These findings illustrate how endogenous viral antigen presentation during persistent viral infection may influence the transcriptional program of virus-specific T cells and their functional profile in the peripheral blood of humans.

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