scholarly journals Streptococcal Pyrogenic Exotoxin A-Stimulated Monocytes Mediate Regulatory T-Cell Accumulation through PD-L1 and Kynurenine

2019 ◽  
Vol 20 (16) ◽  
pp. 3933 ◽  
Author(s):  
Katharina Giesbrecht ◽  
Sandra Förmer ◽  
Aline Sähr ◽  
Klaus Heeg ◽  
Dagmar Hildebrand
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
Inflammatory Cytokines ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Exotoxin A ◽  
T Effector Cells

Bacterial superantigens (SAgs) are exotoxins that promote a fulminant activation of the immune system. The subsequent intense release of inflammatory cytokines often results in hypotension, shock, and organ failure with high mortality rates. In the current paradigm, the direct and simultaneous binding of SAgs with T-cell receptor (TCR)-bearing Vβ regions and conserved structures on major histocompatibility complex class II (MHC class II) on antigen-presenting cells (APCs) induces the activation of both cell types. However, by crosslinking MHC class II molecules, APCs can be activated by SAgs independently of T lymphocytes. Recently, we showed that streptococcal pyrogenic exotoxin A (SPEA) of Streptococcus pyogenes stimulates an immunogenic APC phenotype with upregulated costimulatory molecules and inflammatory cytokines. Additionally, we revealed that SPEA triggers immunosuppressive programs in monocytes that facilitate the accumulation of regulatory T cells (Tregs) in in vitro monocyte/CD4+ T-cell cocultures. Immunosuppressive factors include anti-inflammatory interleukin 10 (IL-10), co-inhibitory surface molecule programmed cell death 1 ligand 1 (PD-L1), and the inhibitory indoleamine 2,3-dioxygenase (IDO)/kynurenine effector system. In the present study, we investigated the underlying mechanism of SPEA-stimulated monocyte-mediated accumulation of Tregs. Blood-derived monocytes from healthy donors were stimulated with SPEA for 48 h (SPEA-monocytes). For the evaluation of SPEA-monocyte-mediated modulation of CD4+ T lymphocytes, SPEA was removed from the culture through extensive washing of cells before adding allogeneic CD3/CD28-activated T cells. Results: In coculture with allogeneic CD4+ T cells, SPEA-monocytes mediate apoptosis of CD4+Foxp3− lymphocytes and accumulation of CD4+Foxp3+ Tregs. PD-L1 and kynurenine are critically involved in the mediated cell death because blocking both factors diminished apoptosis and decreased the proportion of the CD25+/Foxp3+ Treg subpopulation significantly. Upregulation of PD-L1 and kynurenine as well as SPEA-monocyte-mediated effects on T cells depend on inflammatory IL-1β. Our study shows that monocytes activated by SPEA mediate apoptosis of CD4+Foxp3− T effector cells through PD-L1 and kynurenine. CD4+Foxp3+ T cells are resistant to apoptosis and accumulate in SPEA-monocyte/CD4+ T-cell coculture.

scholarly journals Identification of a CD4+ T cell-stimulating antigen of pathogenic bacteria by expression cloning.

1995 ◽  
Vol 182 (6) ◽  
pp. 1751-1757 ◽  
Author(s):  
S Sanderson ◽  
D J Campbell ◽  
N Shastri
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
T Cell ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Pathogenic Bacteria ◽  
Genomic Library ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Expression Cloning

Identifying the immunogenic proteins that elicit pathogen-specific T cell responses is key to rational vaccine design. While several approaches have succeeded in identifying major histocompatibility complex (MHC) class I bound peptides that stimulate CD8+ T cells, these approaches have been difficult to extend to peptides presented by MHC class II molecules that stimulate CD4+ T cells. We describe here a novel strategy for identifying CD4+ T cell-stimulating antigen genes. Using Listeria monocytogenes-specific, lacZ-inducible T cells as single-cell probes, we screened a Listeria monocytogenes genomic library as recombinant Escherichia coli that were fed to macrophages. The antigen gene was isolated from the E. coli clone that, when ingested by the macrophages, allowed generation of the appropriate peptide/MHC class II complex and T cell activation. We show that the antigenic peptide is derived from a previously unknown listeria gene product with characteristics of a membrane-bound protein.

scholarly journals MHC class II-independent CD25+CD4+CD8α β+α β T cells attenuate CD4+T cell-induced transfer colitis

2004 ◽  
Vol 34 (3) ◽  
pp. 705-714 ◽  
Author(s):  
Tamara Krajina ◽  
Frank Leithäuser ◽  
Jörg Reimann
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cd4 T Cell

Human T Cells with Distinct Specificities Mediate Graft-Versus-Leukemia Reactivity and Xenogeneic Graft-Versus-Host Disease in a NOD/Scid Mouse Model for Human Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1330-1330
Author(s):  
Sanja Stevanovic ◽  
Bart Nijmeijer ◽  
Marianke LJ Van Schie ◽  
Roelof Willemze ◽  
Marieke Griffioen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Class I ◽  
T Cell Clones ◽  
Cell Clones ◽  
Human T Cells

Abstract Abstract 1330 Poster Board I-352 Immunodeficient mice inoculated with human leukemia can be used as a model to investigate Graft-versus-Leukemia (GvL) effects of donor lymphocyte infusions (DLIs). In addition to GvL reactivity, treatment with DLI induces xenogeneic Graft-versus-Host Disease (GvHD) in mice, characterized by pancytopenia and weight loss. In patients treated with DLI for relapsed or residual leukemia after allogeneic stem cell transplantation, immune responses against non-leukemic cells may also cause GvHD. It has been suggested that GvL reactivity and GvHD, which co-develop in vivo, can be separated and that distinct T cells exist with the specific capacity to mediate GvL reactivity or GvHD. Since adoptive T cell transfer models that allow analysis of separation of GvL and GvHD are rare, we aimed to establish whether GvL reactivity and xenogeneic GvHD could be separated using our model of human leukemia-engrafted NOD/scid mouse after treatment with human donor T cells. In this study, non-conditioned NOD/scid mice engrafted with primary human acute lymphoblastic leukemic cells were treated with CD3+ DLI. Established tumors were effectively eliminated by emerging human T cells, but also induced xenogeneic GvHD. Flowcytometric analysis demonstrated that the majority of emerging CD8+ and CD4+ T cells were activated (HLA-DR+) and expressed an effector memory phenotype (CD45RA-CD45RO+CCR7-). To investigate whether GvL reactivity and xenogeneic GvHD were mediated by the same T cells showing reactivity against both human leukemic and murine cells, or displaying distinct reactivity against human leukemic and murine cells, we clonally isolated and characterized the T cells during the GvL response and xenogeneic GvHD. T cell clones were analyzed for reactivity against primary human leukemic cells and primary NOD/scid hematopoietic (BM and spleen cells) and non-hematopoietic (skin fibroblasts) cells in IFN-g ELISA. Isolated CD8+ and CD4+ T cell clones were shown to recognize either human leukemic or murine cells, indicating that GvL response and xenogeneic GvHD were mediated by different human T cells. Flowcytometric analysis demonstrated that all BM and spleen cells expressed MHC class I, whereas only 1-3 % of the cells were MHC class II +. Primary skin fibroblasts displayed low MHC class I and completely lacked MHC class II expression. Xeno-reactive CD8+ T cell clones were shown to recognize all MHC class I + target cells and xeno-reactive CD4+ T cells clones displayed reactivity only against MHC class II + target cells. To determine the MHC restriction of xeno-reactive T cell clones, NOD/scid bone marrow (BM) derived dendritic cells (DC) expressing high levels of murine MHC class I and class II were tested for T cell recognition in the presence or absence of murine MHC class I and class II monoclonal antibodies in IFN-g ELISA. Xeno-reactive CD8+ T cell clones were shown to be MHC class I (H-2Kd or H-2Db) restricted, whereas xeno-reactive CD4+ T cell clones were MHC class II (I-Ag7) restricted, indicating that xeno-reactivity reflects genuine human T cell response directed against allo-antigens present on murine cells. Despite production of high levels of IFN-gamma, xeno-reactive CD8+ and CD4+ T cell clones failed to exert cytolytic activity against murine DC, as determined in a 51Cr-release cytotoxicity assay. Absence of cytolysis by CD8+ T cell clones, which are generally considered as potent effector cells, may be explained by low avidity interaction between human T cells and murine DC, since flowcytometric analysis revealed sub-optimal activation of T cells as measured by CD137 expression and T cell receptor downregulation upon co-culture with murine DC, and therefore these results indicate that xenogeneic GvHD in this model is likely to be mediated by cytokines. In conclusion, in leukemia-engrafted NOD/scid mice treated with CD3+ DLI, we show that GvL reactivity and xenogeneic GvHD are mediated by separate human T cells with distinct specificities. All xeno-reactive T cell clones showed genuine recognition of MHC class I or class II associated allo-antigens on murine cells similar as GvHD-inducing human T cells. These data suggest that our NOD/scid mouse model of human acute leukemia may be valuable for studying the effectiveness and specificity of selectively enriched or depleted T cells for adoptive immunotherapy. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Endogenous human cytomegalovirus gB is presented efficiently by MHC class II molecules to CD4+ CTL

2005 ◽  
Vol 202 (8) ◽  
pp. 1109-1119 ◽  
Author(s):  
Nagendra R. Hegde ◽  
Claire Dunn ◽  
David M. Lewinsohn ◽  
Michael A. Jarvis ◽  
Jay A. Nelson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Glial Cells ◽  
Human Cytomegalovirus ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Host Cells ◽  
Cd4 T Cell

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB—expressed by adenovirus vectors or after HCMV infection—and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells.

scholarly journals Severe and multifaceted systemic immunosuppression caused by experimental cancers of the central nervous system requires release of non-steroid soluble mediators

2020 ◽  
Author(s):  
K Ayasoufi ◽  
CK Pfaller ◽  
L Evgin ◽  
RH Khadka ◽  
ZP Tritz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Unknown Etiology ◽  
Thymic Involution ◽  
Cell Counts ◽  
Hallmark Feature

AbstractImmunosuppression of unknown etiology is a hallmark feature of glioblastoma (GBM) and is characterized by decreased CD4 T cell counts and down regulation of MHC class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for GBM. We recapitulated the immunosuppression observed in GBM patients in the C57BL/6 mouse and investigated the etiology of low CD4 T cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of CNS cancer, including mice harboring GL261 glioma, B16 melanoma, and in a spontaneous model of Diffuse Intrinsic Pontine Glioma (DIPG). In addition to thymic involution, we determined that tumor growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC class II expression on hematopoietic cells, and a modest increase in bone marrow resident CD4 T cells with a naïve phenotype. Using parabiosis we report that thymic involution, declines in peripheral T cell counts, and reduced MHC class II expression levels were mediated through circulating blood-derived factors. Conversely, T cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is nonsteroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the aforementioned immunosuppression was not unique to cancer itself, but rather occurs in response to CNS injury. Noncancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that CNS cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity.Short SummaryCNS cancers and other brain-injuries suppress immunity through release of non-steroid soluble factors that disrupt immune homeostasis and dampen responses of the peripheral immune system.Graphical Abstract

scholarly journals Deciphering the Plasmodium falciparum malaria-specific CD4+ T cell response: ex vivo detection of high frequencies of PD-1+TIGIT+ EXP1-specific CD4+ T cells using a novel HLA-DR11-restricted MHC class II tetramer

2021 ◽  
Author(s):  
Sophia Schulte ◽  
Janna Heide ◽  
Christin Ackermann ◽  
Sven Peine ◽  
Michael Ramharter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Class Ii ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Inhibitory Receptors

Abstract Relatively little is known about the ex vivo frequency and phenotype of the P. falciparum-specific CD4+ T cell response in humans. The exported protein 1 (EXP1) is expressed by plasmodia at both, the liver stage and blood stage, of infection making it a potential target for CD4+ and CD8+ effector T cells. Here, a fluorochrome-labelled HLA-DRB1*11:01-restriced MHC class II tetramer derived from the P. falciparum EXP1 (aa62-74) was established for ex vivo tetramer analysis and magnetic bead enrichment in ten patients with acute malaria. EXP1-specific CD4+ T cells were detectable in nine out of ten (90%) malaria patients expressing the HLA-DRB1*11 molecule with an average ex vivo frequency of 0.11% (0-0.22%) of total CD4+ T cells. The phenotype of EXP1-specific CD4+ T cells was further assessed using co-staining with activation (CD38, HLA-DR, CD26), differentiation (CD45RO, CCR7, KLRG1, CD127), senescence (CD57) and co-inhibitory (PD-1, TIGIT, LAG-3, TIM-3) markers as well as the ectonucleotidases CD39 and CD73. EXP1-specific tetramer+ CD4+ T cells had a distinct phenotype compared to bulk CD4+ T cells and displayed a highly activated effector memory phenotype with elevated levels of co-inhibitory receptors and activation markers: EXP1-specific CD4+ T cells universally expressed the co-inhibitory receptors PD-1 and TIGIT as well as the activation marker CD38 and showed elevated frequencies of CD39. These results demonstrate that MHC class II tetramer enrichment is a sensitive approach to investigate ex vivo antigen-specific CD4+ T cells in malaria patients that will aid further analysis of the role of CD4+ T cells during malaria.

scholarly journals Essential yet limited role for CCR2+ inflammatory monocytes during Mycobacterium tuberculosis-specific T cell priming

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Miriam Samstein ◽  
Heidi A Schreiber ◽  
Ingrid M Leiner ◽  
Bože Sušac ◽  
Michael S Glickman ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Lymph Nodes ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Inflammatory Monocytes ◽  
T Cell Priming

Defense against infection by Mycobacterium tuberculosis (Mtb) is mediated by CD4 T cells. CCR2+ inflammatory monocytes (IMs) have been implicated in Mtb-specific CD4 T cell responses but their in vivo contribution remains unresolved. Herein, we show that transient ablation of IMs during infection prevents Mtb delivery to pulmonary lymph nodes, reducing CD4 T cell responses. Transfer of MHC class II-expressing IMs to MHC class II-deficient, monocyte-depleted recipients, while restoring Mtb transport to mLNs, does not enable Mtb-specific CD4 T cell priming. On the other hand, transfer of MHC class II-deficient IMs corrects CD4 T cell priming in monocyte-depleted, MHC class II-expressing mice. Specific depletion of classical DCs does not reduce Mtb delivery to pulmonary lymph nodes but markedly reduces CD4 T cell priming. Thus, although IMs acquire characteristics of DCs while delivering Mtb to lymph nodes, cDCs but not moDCs induce proliferation of Mtb-specific CD4 T cells.

scholarly journals Different superantigens interact with distinct sites in the Vbeta domain of a single T cell receptor.

1996 ◽  
Vol 183 (4) ◽  
pp. 1437-1446 ◽  
Author(s):  
S C Hong ◽  
G Waterbury ◽  
C A Janeway
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Mutational Analysis ◽  
Gene Segment ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Published Data ◽  
Antigenic Peptides ◽  
Mhc Class Ii Molecules

CD4 T cell receptors (TCRs) recognize antigenic peptides presented by self major histocompatibility complex (MHC) class II molecules as well as non-self MHC class II molecules. The TCRs can also recognize endogenous retroviral gene products and bacterial toxins known collectively as superantigens (SAGs) that act mainly on the Vbeta gene segment-encoded portion of the Vbeta domain; most SAGs also require MHC II class for presentation. We have studied the interaction of the TCR from a well-characterized CD4 T cell line with SAGs by mutational analysis of its Vbeta domain. This appears to separate viral (v)SAG from bacterial (b)SAG recognition. T cells having a TCR with glycine to valine mutation in amino acid residue 51 (G51V) in complementarity determining region 2 of the TCR Vbeta domain fail to respond the bSAGs staphylococcal enterotoxin B (SEB), SEC1, SEC2, and SEC3, whereas they retain the ability to respond to non-self MHC class II molecules and to foreign peptides presented by self MHC class II molecules. It is interesting to note that T cells expressing mutations of both G51V and G53D of V beta regain the response to SEB and partially that to SEC1, but do not respond to SEC2, and SEC3, suggesting that different bacterial SAGs are viewed differently by the same TCR. These results are surprising, because it has been generally believed that SAG recognition by T cells is mediated exclusively by hypervariable region 4 on the exposed, lateral face of the TCR Vbeta domain. Response to the vSAG Mtv-7 was generated by mutation in Vbeta residue 24 (N24H), confirming previously published data. These data show that the vSAG Mtv-7 and bSAGs are recognized by different regions of the TCR Vbeta domain. In addition, various bSAGs are recognized differently by the same TCR. Thus, these mutational data, combined with the crystal structure of the TCR beta chain, provide evidence for distinct recognition sites for vSAG and bSAG.

Vaccine-Induced, Pseudorabies Virus-Specific, Extrathymic CD4+CD8+ Memory T-Helper Cells in Swine

1998 ◽  
Vol 72 (6) ◽  
pp. 4866-4873 ◽  
Author(s):  
Bertram T. Ober ◽  
Artur Summerfield ◽  
Christina Mattlinger ◽  
Karl-Heinz Wiesmüller ◽  
Günther Jung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
T Helper Cells ◽  
Pseudorabies Virus ◽  
Class Ii ◽  
T Cell Epitopes ◽  
T Helper ◽  
Helper Cells

ABSTRACT Pseudorabies virus (PRV; suid herpesvirus 1) infection causes heavy economic losses in the pig industry. Therefore, vaccination with live attenuated viruses is practiced in many countries. This vaccination was demonstrated to induce extrathymic virus-specific memory CD4+CD8+ T lymphocytes. Due to their major histocompatibility complex (MHC) class II-restricted proliferation, it is generally believed that these T lymphocytes function as memory T-helper cells. To directly prove this hypothesis, 15-amino-acid, overlapping peptides of the viral glycoprotein gC were used for screening in proliferation assays with peripheral blood mononuclear cells of vaccinated d/d haplotype inbred pigs. In these experiments, two naturally processed T-cell epitopes (T1 and T2) which are MHC class II restricted were identified. It was shown that extrathymic CD4+CD8+ T cells are the T-lymphocyte subpopulation that responds to epitope T2. In addition, we were able to show that cytokine secretion can be induced in these T cells through recall with inactivated PRV and demonstrated that activated PRV-primed CD4+CD8+ T cells are able to induce PRV-specific immunoglobulin synthesis by PRV-primed, resting B cells. Taken together, these results demonstrate that the glycoprotein gC takes part in the priming of humoral anti-PRV memory responses. The experiments identified the first T-cell epitopes so far known to induce the generation of virus-specific CD4+CD8+ memory T lymphocytes and showed that CD4+CD8+ T cells are memory T-helper cells. Therefore, this study describes the generation of virus-specific CD4+CD8+ T cells, which is observed during vaccination, as a part of the potent humoral anti-PRV memory response induced by the vaccine.

scholarly journals CD4 T-Cell Suppression by Cells from Toxoplasma gondii-Infected Retinas Is Mediated by Surface Protein PD-L1

2010 ◽  
Vol 78 (8) ◽  
pp. 3484-3492 ◽  
Author(s):  
Elizabeth Charles ◽  
Sunil Joshi ◽  
John D. Ash ◽  
Barbara A. Fox ◽  
A. Darise Farris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Flow Cytometric Analysis ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Dependent Manner ◽  
Retinal Cells

ABSTRACT In the inflamed retina, CD4+ T cells can cause retinal damage when they are not properly regulated. Since tissue expression of major histocompatibility complex (MHC) class II and costimulatory molecules is a key mechanism for regulating effector T cells, we tested the hypothesis that upregulation of these proteins in the retina contributes to the regulation of CD4 T cells. Here we report that in retinas infected with the protozoan parasite Toxoplasma gondii, MHC class II is upregulated on infiltrating leukocytes as well as on resident retinal cells, including photoreceptors. Flow cytometric analysis indicated that B7 costimulatory family members (CD80, CD86, ICOS-L, and programmed death ligand 2 [PD-L2]) were not expressed on class II+ cells. In contrast, PD-L1 (also named B7-H1 or CD274) was expressed on the majority of both hematopoietic and resident retinal MHC class II-expressing cells. Retinal cells from Toxoplasma-infected animals were able to suppress T-cell activation in a PD-L1-dependent manner. Finally, we demonstrate that the expression of MHC class II and PD-L1 was critically dependent on gamma interferon (IFN-γ) expression. These data suggest that retinal MHC class II and PD-L1 expression is a novel mechanism by which the retina protects itself from CD4 T-cell-mediated immune damage in ocular toxoplasmosis and other types of retinal immune responses.

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