Immunoregulation of lymphoproliferation in vitro by monocytes and their subpopulations. I. The induction of suppressor T cells in long term cultures and the role of MHC class II determinants and preliminary characteristics

1988 ◽  
Vol 18 (4) ◽  
pp. 275-280 ◽  
Author(s):  
M. Zembala ◽  
J. Pryjma ◽  
I. Ruggiero ◽  
W. Uracz
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Suppressor T Cells

scholarly journals Role of CD4 in thymocyte selection and maturation.

1989 ◽  
Vol 169 (6) ◽  
pp. 2085-2096 ◽  
Author(s):  
J C Zuñiga-Pflücker ◽  
S A McCarthy ◽  
M Weston ◽  
D L Longo ◽  
A Singer ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Decisive Role ◽  
Class Ii ◽  
Double Positive ◽  
Adult Mice

We examined the possible role of CD4 molecules during in vivo and in vitro fetal thymic development. Our results show that fetal thymi treated with intact anti-CD4 mAbs fail to generate CD4 single-positive T cells, while the generation of the other phenotypes remains unchanged. Most importantly, the use of F(ab')2 and Fab anti-CD4 mAb gave identical results, i.e., failure to generate CD4+/CD8- T cells, with no effect on the generation of CD4+/CD8+ T cells. Since F(ab')2 and Fab anti-CD4 fail to deplete CD4+/CD8- in adult mice, these results strongly argue that the absence of CD4+/CD8- T cells is not due to depletion, but rather, is caused by a lack of positive selection, attributable to an obstructed CD4-MHC class II interaction. Furthermore, we also observed an increase in TCR/CD3 expression after anti-CD4 (divalent or monovalent) mAb treatment. The TCR/CD3 upregulation occurs in the double-positive population, and may result from CD4 signaling after mAb engagement, or may be a consequence of the blocked CD4-class II interactions. One proposed model argues that the CD3 upregulation occurs in an effort to compensate for the reduction in avidity or signaling that is normally provided by the interaction of the CD4 accessory molecule and its ligand. As a whole, our findings advocate that CD4 molecules play a decisive role in the differentiation of thymocytes.

scholarly journals Major histocompatibility complex-restricted recognition of retroviral superantigens by V beta 17+ T cells.

1992 ◽  
Vol 176 (1) ◽  
pp. 275-280 ◽  
Author(s):  
M A Blackman ◽  
F E Lund ◽  
S Surman ◽  
R B Corley ◽  
D L Woodland
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Direct Role ◽  
Histocompatibility Complex ◽  
Class Ii Mhc ◽  
Mhc Class Ii Molecules

It has been established that at least some V beta 17+ T cells interact with an endogenous superantigen encoded by the murine retrovirus, Mtv-9. To analyze the role of major histocompatibility complex (MHC) class II molecules in presenting the Mtv-9 encoded superantigen, vSAG-9 to V beta 17+ hybridomas, a panel of nine hybridomas was tested for their ability to respond to A20/2J (H-2d) and LBK (H-2a) cells which had been transfected with the vSAG-9 gene. Whereas some of the hybridomas recognized vSAG-9 exclusively in the context of H-2a, other hybridomas recognized vSAG-9 exclusively in the context of H-2d or in the context of both H-2d and H-2a. These results suggest that: (a) the class II MHC molecule plays a direct role in the recognition of retroviral superantigen by T cells, rather than serving simply as a platform for presentation; and, (b) it is likely that components of the TCR other than V beta are involved in the vSAG-9/TCR/class II interaction.

Donor CD4+CD25+ T Cells Require Syngeneic MHC Class II for Initial Support of MHC-Mismatched Hematopoietic Engraftment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 251-251 ◽  
Author(s):  
Alan Hanash ◽  
Robert B. Levy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Allogeneic Bone Marrow Transplantation ◽  
Class Ii ◽  
Allogeneic Bone ◽  
Inherited Disorders ◽  
Donor Chimerism

Abstract Despite the potential to cure both acquired and inherited disorders involving the hematopoietic compartment, application of allogeneic bone marrow transplantation (BMT) is limited by the frequent and severe outcome of Graft vs. Host Disease (GVHD). Unfortunately, efforts to reduce GVHD by purging the donor graft of T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic engraftment without inducing GVHD could increase the potential for donor-recipient matching and decrease treatment associated risks. We have observed that GVHD-suppressive donor CD4+CD25+ T cells are capable of supporting allogeneic hematopoietic engraftment, as demonstrated by initial donor progenitor activity and long-term chimerism and tolerance. Using a murine MHC mismatched model transplanting 0.5–2x106 GFP+ C57BL/6 (B6) T cell-depleted bone marrow cells into 7.0 Gy sublethally irradiated BALB/c recipients, splenic CFU assessment demonstrated that co-transplantation of 1x106 B6 CD4+CD25+ T cells lead to increased donor lineage-committed GM (p<.01) and multi-potential HPP (p<.05) progenitors seven days post-BMT compared to transplantation of BM alone. Furthermore, co-transplantation of CD4+CD25+ T cells lead to lymphoid and myeloid chimerism in peripheral blood (lineage specific mean donor chimerism ± SE: B220, 67.7±15.2 vs. 0.3±0.3; CD4, 38.3±10.5 vs.0.9±0.9; CD8, 48.3±11.0 vs. 1.0±1.0; Mac-1, 58.8±16.5 vs. 0.3±0.3) and the presence of donor GM and HPP progenitors in recipient marrow two months post-BMT (mean CFU chimerism ± SE: CFU-GM, 54.5±12.8 vs. 0.0; CFU-HPP, 63.0±17.8 vs.0.0). Donor chimerism persisted six months post-BMT and was associated with tolerance to donor and host antigens by acceptance of donor and host skin grafts >50 days post-homotopic grafting. Characterization of the initial invents of engraftment support demonstrated that augmentation of donor progenitors did not require CD4+CD25+ T cell IL-10, as co-transplantation of B6-wt and B6-IL-10−/− CD4+CD25+ T cells both significantly increased total CFU-GM (mean CFU±SE: BM alone, 657.5±248.2; BM + wt, 1972±331.5; BM + IL-10−/−, 1965±401.7; both p<.05 vs. BM alone). Assessment of the antigenic requirements for activation of progenitor support demonstrated that donor CD4+CD25+ T cells did not require alloreactivity to support progenitors, as BALB/c x B6 F1 CD4+CD25+ T cells significantly increased B6 CFU-GM in BALB/c recipients (p<.001 vs. BM alone). However, B6 CD4+CD25+ T cells failed to augment C3H/HeJ CFU-GM in BALB/c recipients (p>.05 vs. BM alone), suggesting that donor CD4+CD25+ T cells might require recognition of syngeneic MHC for progenitor support. Indeed, augmentation of donor CFU-GM was abrogated when B6 CD4+CD25+ T cells were co-transplanted with B6-MHC class II−/− marrow into BALB/c recipients (p>.05 vs. BM alone). In conclusion, donor CD4+CD25+ T cells capable of promoting long-term engraftment and tolerance do not require IL-10 for support of initial donor progenitor activity, however progenitor support does require co-transplantation with syngeneic MHC class II expressing marrow. Donor CD4+CD25+ T cells may thus represent a useful alternative to unfractionated T cells for promotion of engraftment following allogeneic hematopoietic transplantation.

Absence of STAT1 Signaling in Host Hematopoietic Cells Leads to Enhanced Gvhd Induction and Involves Increased Expression of MHC Class II and Reduced PD-L1 Expression on Dendritic Cells,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4026-4026
Author(s):  
Caisheng Lu ◽  
Huihui Ma ◽  
Ailing Liu ◽  
MeiHua Jin ◽  
Shirong Li ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Cell Activation ◽  
Hematopoietic Cells ◽  
Class Ii ◽  
Cfse Dilution ◽  
Stat1 Signaling ◽  
Donor Lymphocytes

Abstract Abstract 4026 Interferon-g/STAT1 signaling plays a critical role in regulating dendritic cell activation and function. Blockade of IFN-g signaling leads to reduced DC activation and impaired anti-tumor and acquired adaptive immunity. We recently reported that lack of IFN-g/STAT1 in donor lymphocytes leads to reduced GVHD induction in both MHC- and mHA-mismatched mouse BMT models. In this study, we addressed the role of host STAT1 in the regulation of GVHD. Wildtype or STAT1-deficient 129 mice (H2b) underwent allogeneic Bone Marrow Transplantation (BMT) following lethal irradiation (1044 rad). GVHD was induced using either BALB/c or B6 donor spleen cells. We unexpectedly observed that absence of STAT1 in recipient mice led to increased GVHD-associated mortality in both MHC-mismatched (MST 5 vs. 8, p=0.01) and mHA-mismatched (MST 11 vs. 23, p<0.01) BMT settings. The enhanced GVHD induction was found to be associated with increased activation (expression of CD69 and CD25) and allo-antigen driven proliferation of donor CD4 and CD8 T cells as determined by CFSE-dilution. As host APCs have been reported to being crucial for induction of GVHD, we phenotypically and functionally characterized STAT1 deficient DCs. Our studies revealed that STAT1-deficient bone marrow-derived dendritic cells (BMDCs) which were maturated in the presence of LPS showed significantly increased MHC class II, CD86, CD80 and CD40 expression compared with wildtype BMDCs. Furthermore, STAT1-deficient BMDC showed significantly increased direct allo-stimulatory capacity resulting in increased responder cell proliferation as determined by standard MLR assays using 3H-Thymidine uptake assays as well as CFSE-dilution studies. STAT1−/− BMDCs significantly promoted CD44+CD62L- expression in responder CD4 and CD8 T cells compared to wild type BMDCs (all p<0.001). The increased MHC II expression in STAT1-deficient DC was further confirmed in host CD11b+ and CD11c+ cells following GVHD induction in vivo. To determine whether non-hematopoietic cells in STAT1−/− host contribute to the increased GVHD induction, we created radiation chimeras in which STAT1 was only deficient in the hematopoietic compartment by transplanting 129.STAT1−/− BMC into 129.STAT1+/+ recipients following lethal irradiation. 120 days later GVHD was induced using fully MHC-mismatched BALB/c donor splenocytes. Similar to STAT1-deficient recipients STAT1−/− ®WT chimeras showed enhanced GVHD induction compared to STAT1+/+®WT chimeras (MST 11 vs. 5, p<0.05). To determine the mechanism underlying the enhanced expansion of donor T cells in response to stimulation with STAT1-deficient APC, we hypothesized that STAT-deficiency may impair expression of the T cell inhibitory molecules Programed Cell Death-Ligand1 or-2 (PD-L1,-L2) on APC. We therefore studied the expression of PD-L1 and PD-L2 expression on wildtype and STAT1-deficient DC. Indeed, were able to demonstrate that absence of STAT1 significantly suppressed PD-L1 expression on BMDCs upon in vitro LPS stimulation (Mean Fluorescence Intensity 167.2± 15.9 vs. 532.5±7.6, p<0.001) and also in vivo tested on day+ 6 post-BMT in the mHA-mismatched setting. In line with these results using in vitro stimulation we could demonstrate significantly reduced Activation Induced Cell Death (AICD) in activated B6.SJL CD69+ CD4 and CD8 cells stimulated with 129.STAT1−/− BMDCs compared to cells stimulated with 129.STAT1+/+ BMDCs (10.6±1.5% vs. 28.2±1.9 % for CD4; 13.0±0.7% vs. 30.5±1.1% for CD8 respectively, p<0.001 for all). Importantly, blocking IFN-g with neutralizing antibodies significantly increased MHC class II, CD86 expression and reduced reduced PD-L1 expression on BMDCs upon LPS stimulation. In summary, our data suggest two mechanisms how the absence of STAT1 signaling in host hematopoietic cells may promote the development of GVHD: First, increased expression of MHC II and co-stimulatory molecule in STAT1-deficient APC may lead to enhanced activation and proliferation of donor lymphocytes. Second, absence of STAT1 in maturated host DC inhibits PD-L1 expression thus leading to reduced AICD of activated donor lymphocytes. These findings suggest that STAT1-signaling modulates host APC function and shapes the GVH-response by causing increased allo-antigen-specific donor T cell activation, survival and proliferation. Disclosures: Lentzsch: Centocor Ortho Biotech: Research Funding; Genzyme: Consultancy; Onyx: Consultancy; Celgene: Consultancy, Research Funding.

In vitro synthesis of antibodies to acetylcholine receptor by peripheral blood cells: Role of suppressor T cells in normal subjects

Neurology ◽  
1984 ◽  
Vol 34 (6) ◽  
pp. 802-802 ◽  
Author(s):  
R. P. Lisak ◽  
C. Laramore ◽  
A. I. Levinson ◽  
B. Zweiman ◽  
A. R. Moskovitz ◽  
...  
Keyword(s):  
T Cells ◽  
Acetylcholine Receptor ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Normal Subjects ◽  
Peripheral Blood Cells ◽  
Suppressor T Cells ◽  
In Vitro Synthesis

Role of MHC class II expressing CD4+ T cells in proteolipid protein91–110-induced EAE in HLA-DR3 transgenic mice

2006 ◽  
Vol 36 (12) ◽  
pp. 3356-3370 ◽  
Author(s):  
Ashutosh Mangalam ◽  
Moses Rodriguez ◽  
Chella David
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Hla Dr3

scholarly journals Migratory Activation of Primary Cortical Microglia upon Infection with Toxoplasma gondii

2011 ◽  
Vol 79 (8) ◽  
pp. 3046-3052 ◽  
Author(s):  
Isabel Dellacasa-Lindberg ◽  
Jonas M. Fuks ◽  
Romanico B. G. Arrighi ◽  
Henrik Lambert ◽  
Robert P. A. Wallin ◽  
...  
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Mhc Class Ii ◽  
Glial Cells ◽  
Costimulatory Molecule ◽  
Toxoplasmic Encephalitis ◽  
Immune Functions ◽  
Content Type

ABSTRACTDisseminated toxoplasmosis in the central nervous system (CNS) is often accompanied by a lethal outcome. Studies with murine models of infection have focused on the role of systemic immunity in control of toxoplasmic encephalitis, while knowledge remains limited on the contributions of resident cells with immune functions in the CNS. In this study, the role of glial cells was addressed in the setting of recrudescentToxoplasmainfection in mice. Activated astrocytes and microglia were observed in the close vicinity of foci with replicating parasitesin situin the brain parenchyma.Toxoplasma gondiitachyzoites were allowed to infect primary microglia and astrocytesin vitro. Microglia were permissive to parasite replication, and infected microglia readily transmigrated across transwell membranes and cell monolayers. Thus, infected microglia, but not astrocytes, exhibited a hypermotility phenotype reminiscent of that recently described for infected dendritic cells. In contrast to gamma interferon-activated microglia,Toxoplasma-infected microglia did not upregulate major histocompatibility complex (MHC) class II molecules and the costimulatory molecule CD86. YetToxoplasma-infected microglia and astrocytes exhibited increased sensitivity to T cell-mediated killing, leading to rapid parasite transfer to effector T cellsin vitro. We hypothesize that glial cells and T cells, besides their role in triggering antiparasite immunity, may also act as “Trojan horses,” paradoxically facilitating dissemination ofToxoplasmawithin the CNS. To our knowledge, this constitutes the first report of migratory activation of a resident CNS cell by an intracellular parasite.

scholarly journals Neoleukin-2 enhances anti-tumour immunity downstream of peptide vaccination targeted by an anti-MHC class II VHH

Open Biology ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 190235 ◽  
Author(s):  
Stephanie J. Crowley ◽  
Patrick T. Bruck ◽  
Md Aladdin Bhuiyan ◽  
Amelia Mitchell-Gears ◽  
Michael J. Walsh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class Ii ◽  
Tumour Immunity ◽  
Tumour Rejection

Cancer-specific mutations can lead to peptides of unique sequence presented on MHC class I to CD8 T cells. These neoantigens can be potent tumour-rejection antigens, appear to be the driving force behind responsiveness to anti-CTLA-4 and anti-PD1/L1-based therapies and have been used to develop personalized vaccines. The platform for delivering neoantigen-based vaccines has varied, and further optimization of both platform and adjuvant will be necessary to achieve scalable vaccine products that are therapeutically effective at a reasonable cost. Here, we developed a platform for testing potential CD8 T cell tumour vaccine candidates. We used a high-affinity alpaca-derived VHH against MHC class II to deliver peptides to professional antigen-presenting cells. We show in vitro and in vivo that peptides derived from the model antigen ovalbumin are better able to activate naive ovalbumin-specific CD8 T cells when conjugated to an MHC class II-specific VHH when compared with an irrelevant control VHH. We then used the VHH-peptide platform to evaluate a panel of candidate neoantigens in vivo in a mouse model of pancreatic cancer. None of the candidate neoantigens tested led to protection from tumour challenge; however, we were able to show vaccine-induced CD8 T cell responses to a melanoma self-antigen that was augmented by combination therapy with the synthetic cytokine mimetic Neo2/15.

Double Loading of Dendritic Cell MHC Class I and MHC Class II with an AML Antigen Repertoire Enhances Primary and Secondary T-Cell Responses In Vitro.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2529-2529
Author(s):  
William K. Decker ◽  
Dongxia Xing ◽  
Sufang Li ◽  
Simon N. Robinson ◽  
Hong Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cd8 T Cells ◽  
Class Ii ◽  
T Cell Response ◽  
Class I ◽  
Cross Presentation ◽  
Ifn Γ

Abstract Despite improvements in therapy for acute myelogenous leukemia (AML), a significant percentage of patients still relapse and succumb to their disease. Dendritic cell immunotherapy offers the promise of potentially effective supportive therapy for a variety of neoplastic conditions; and the use of DCs loaded with tumor antigens is now recognized as an important investigational therapy. Though a variety of methods have been used to load DC vaccines, the loading of the MHC class II compartment with tumor lysate has predominated. The priming of a class II-mediated (CD4) T-cell response may be crucial to the success of DC immunotherapy as such a response is likely required for the development of memory CD8+ T-cells. DC cross-presentation is credited with the ability of lysate-loaded DCs to prime both CD4 and CD8 T-cell responses, enabling the generation of CD8+ CTLs without the loading of the MHC class I compartment (i.e. the cytoplasm). Recently, however, several reports have raised doubts as to the efficiency of cross-presentation as a mechanism for CTL priming in vivo. To examine this issue, we have loaded human DCs with both AML tumor lysate and mRNA. This technique allows the full repertoire of class I antigens to be presented without dependence upon cross-presentation; and, moreover, provides a full complement of class II antigens necessary for CD4 T-cell priming and the generation of memory responses. Methods: CD14+ precursors were isolated from normal donor PBPCs by magnetic separation. Immature DCs were then generated by culturing precursors for six days in GM-CSF and IL-4. Lysate was produced by three successive freeze/thaw cycles of blasts. mRNA was extracted from blasts using Trizol and oligo-dT separation. Immature DCs were pulsed for three hours with AML lysate and subsequently electroporated with AML mRNA. Loaded DCs were matured for 48 hours with IL-1β, TNF-α, IL-6, and PGE2 and then used to prime autologous T-cells. Short-term responses were assayed on day 5 of the 1st stimulation. Memory responses were assayed on day 10 of a tertiary stimulation. Results: Doubly-loaded DCs can prime a superior T-cell response in vitro in comparison to that of singly-loaded DCs, demonstrating a 30–70% increase in IFN-γ ELISpots over lysate-loaded DCs (p&lt;0.001) and a 3–4 fold increase in ELISpots in comparison to mRNA loaded DCs (p&lt;0.001). These results were verified by flow cytometry which showed 35% of CD8+ T-cells primed by doubly-loaded DCs were CD69+/IFN-γ+ vs. 14% of CD8+ T-cells primed by lysate-loaded DCs (p&lt;0.001). This enhancement may be based upon both an upregulation of CD83 surface expression (p&lt;0.0019) of doubly-loaded DCs and/or the upregulation of B7.1/B7.2 that accompanies elevated CD40L signaling. Memory responses were also greatly improved, with a 126% increase in total ELISpots (double loaded DCs versus lysate loaded DCs; p&lt;0.03) and a 187% increase in total IFN-γ secretion (p&lt;0.03). Unloaded (p&lt;0.01) and mRNA (p&lt;0.007) loaded DCs exhibited a virtual inability to generate memory T-cells in vitro, suggesting that the perpetuation of the memory response is reliant upon T-cell help. Conclusion: DCs doubly-loaded with lysate and mRNA are more efficient in the generation of primary and secondary immune responses than are singly-loaded DCs. The clinical administration of such doubly-loaded DCs may offer an important therapeutic option to patients with AML.

Sign in / Sign up

Export Citation Format

Share Document