scholarly journals Tonsillar Cancer with High CD8+ T-Cell Infiltration Features Increased Levels of Dendritic Cells and Transcriptional Regulation Associated with an Inflamed Tumor Microenvironment

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5341
Author(s):  
David Gomez Jimenez ◽  
Aastha Sobti ◽  
David Askmyr ◽  
Christina Sakellariou ◽  
Sofia Carreira Santos ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Rna Sequencing ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
Sequencing Data ◽  
Tonsillar Cancer ◽  
Antigen Presenting

Human papillomavirus (HPV) is the main causal agent of tonsillar cancer (TC) and HPV+ TC has a favorable prognosis compared to HPV– disease. In this study, we examined aspects of the tumor microenvironment of TC, focusing on T-cells, dendritic cells (DC), and macrophages. Fresh biopsies of TC and the contralateral healthy tonsil (HT) were obtained from 20 patients, analyzed by multiparameter flow cytometry, and assessed against a detailed HPV-status. Additionally, RNA-sequencing data from 38 TC samples available in the public database, The Cancer Genome Atlas (TCGA), were explored, focusing on the same leukocyte populations. HPV+ TC featured increased levels of CD8+ T-cells and antigen-presenting cells (cf. HPV– TC and HT, respectively). In HPV+ TC, CD8+ T-cell frequencies correlated to DC levels independently of tumor stage, HPV 16 copy number, and E7 oncogene expression as well as frequencies of other leukocytes. Similarly, RNA sequencing data were explored by dividing the HPV+ TCs according to predefined CD8+ T-cell scores in silico. Higher levels of genes expressed by antigen-presenting cells and effector T-cells, such as immune checkpoints and cytokines, were detected in the CD8HIGH HPV+ TC samples (cf. CD8LOW HPV+ TC). In conclusion, CD8HIGH HPV+ TC displays a unique inflammatory profile associated with increased effector T-cell functions and the presence of antigen-presenting cells in the tumor microenvironment. Further studies are warranted to assess if this information can be used on an individual basis to aid in prognosis and treatment decisions.

scholarly journals T Cells Compete for Access to Antigen-Bearing Antigen-Presenting Cells

2000 ◽  
Vol 192 (8) ◽  
pp. 1105-1114 ◽  
Author(s):  
Ross M. Kedl ◽  
William A. Rees ◽  
David A. Hildeman ◽  
Brian Schaefer ◽  
Tom Mitchell ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Secondary Response ◽  
Cell Responses ◽  
Antigen Presenting

These studies tested whether antigenic competition between T cells occurs. We generated CD8+ T cell responses in H-2b mice against the dominant ovalbumin epitope SIINFEKL (ova8) and subdominant epitope KRVVFDKL, using either vaccinia virus expressing ovalbumin (VV-ova) or peptide-pulsed dendritic cells. CD8+ T cell responses were visualized by major histocompatibility complex class I–peptide tetrameric molecules. Transfer of transgenic T cells with high affinity for ova8 (OT1 T cells) completely inhibited the response of host antigen-specific T cells to either antigen, demonstrating that T cells can directly compete with each other for response to antigen. OT1 cells also inhibited CD8+ T cell responses to an unrelated peptide, SIYRYGGL, providing it was presented on the same dendritic cells as ova8. These inhibitions were not due to a more rapid clearance of virus or antigen-presenting cells (APCs) by the OT1 cells. Rather, the inhibition was caused by competition for antigen and antigen-bearing cells, since it could be overcome by the injection of large numbers of antigen-pulsed dendritic cells. These results imply that common properties of T cell responses, such as epitope dominance and secondary response affinity maturation, are the result of competitive interactions between antigen-bearing APC and T cell subsets.

scholarly journals Dendritic cells are potent antigen-presenting cells for microbial superantigens.

1992 ◽  
Vol 175 (1) ◽  
pp. 267-273 ◽  
Author(s):  
N Bhardwaj ◽  
S M Friedman ◽  
B C Cole ◽  
A J Nisanian
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Antigen Presenting Cells ◽  
Small Subset ◽  
Cell Functions ◽  
Cell Responses ◽  
Antigen Presenting

Dendritic cells are a small subset of human blood mononuclear cells that are potent stimulators of several T cell functions. Here we show they are 10-50-fold more potent than monocytes or B cells in inducing T cell responses to a panel of superantigens. Furthermore, dendritic cells can present femtomolar concentrations of superantigen to T cells even at numbers where other antigen-presenting cells (APCs) are inactive. Although dendritic cells express very high levels of the major histocompatibility complex products that are required to present superantigens, it is only necessary to pulse these APCs for 1 hour with picomolar levels of one superantigen, staphylococcal enterotoxin B, to maximally activate T cells. Our results suggest that very small amounts of superantigen will be immunogenic in vivo if presented on dendritic cells.

CD8 T-Cell Infiltration in Extravascular Tissues of Patients With Human Immunodeficiency Virus Infection. Interleukin-15 Upmodulates Costimulatory Pathways Involved in the Antigen-Presenting Cells–T-Cell Interaction

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1277-1286 ◽  
Author(s):  
Carlo Agostini ◽  
Renato Zambello ◽  
Monica Facco ◽  
Alessandra Perin ◽  
Francesco Piazza ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Binding Proteins ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Antigen Presenting

Interleukin (IL)-15 regulates the proliferative activity of the CD8+ T-cell pool in human immunodeficiency virus (HIV)-infected patients, thereby contributing to the maintenance of the CD8+ T-cell–mediated immune response against HIV in extravascular tissues, including the lung. However, the effects of IL-15 on antigen-presenting cells (APC) during HIV infection are still unclear. In this study, we evaluated whether IL-15 regulates the macrophage stimulatory pathways governing inflammatory events that take place in the lung of patients with HIV infection. As a first step we evaluated the in vitro effects of IL-15 on lung macrophages retrieved from the respiratory tract of eight normal subjects. Although macrophages from uninfected individuals expressed the IL-15 binding proteins (IL-15R and the common γc) at resting conditions, they did not express IL-15 messenger RNA (mRNA). However, a 24-hour stimulation with IL-15 induced the expression of interferon-γ (IFN-γ) and IL-15 itself, suggesting a role for this cytokine in the activation of the pulmonary macrophage pool during inflammation. As a confirmation of the role of IL-15 in this setting, at resting conditions, alveolar macrophages of patients with HIV infection and T-cell alveolitis expressed IL-15, IFN-γ, and IL-15 binding proteins; showed an upmodulation of costimulatory molecules, B7 and CD72, which are involved in the APC of macrophages; and behaved as effective accessory cells because they elicited a strong proliferation of T cells. The accessory effect was inhibited by pretreatment with anti-CD72, anti-B7 (CD80 and CD86), and anti–IL-15 monoclonal antibodies (MoAb). We then investigated the relationship between IL-15 and the expression of costimulatory molecules by macrophages. A 24-hour stimulation of IL-15R+/γc+ macrophages with IL-15 upregulated the expression of CD80 and CD86. The evidence that IL-15 upregulates the expression of coligands that favor the contact between T cells and APC, per se, triggers T-cell activation and proliferation and acts as a chemoattractant for T cells, suggests that IL-15 plays a key role in Tc1-mediated defense mechanisms taking place in extravascular tissues of patients with HIV disease.

scholarly journals Uptake of HLA Alloantigens via CD89 and CD206 Does Not Enhance Antigen Presentation by Indirect Allorecognition

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Eytan Breman ◽  
Jurjen M. Ruben ◽  
Kees L. Franken ◽  
Mirjam H. M. Heemskerk ◽  
Dave L. Roelen ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Antigen Presenting Cells ◽  
Mannose Receptor ◽  
Class Ii ◽  
Hla Class Ii ◽  
Indirect Allorecognition ◽  
Antigen Presenting

In organ transplantation, alloantigens are taken up by antigen presenting cells and presented via the indirect pathway to T-cells which in turn can induce allograft rejection. Monitoring of these T-cells is of major importance; however no reliable assay is available to routinely monitor indirect allorecognition. Recently we showed that HLA monomers can be successfully used to monitor indirect allorecognition. Targeting antigens to endocytic receptors on antigen presenting cells may further enhance the presentation of antigens via HLA class II and improve the efficiency of this assay. In the current study we explored targeting of HLA monomers to either CD89 expressing monocytes or mannose receptor expressing dendritic cells. Monomer-antibody complexes were generated using biotin-labeled monomers and avidin labeling of the antibodies. We demonstrate that targeting the complexes to these receptors resulted in a dose-dependent HLA class II mediated presentation to a T-cell clone. The immune-complexes were efficiently taken up and presented to T-cells. However, the level of T-cell reactivity was similar to that when only exogenous antigen was added. We conclude that HLA-A2 monomers targeted for presentation through CD89 on monocytes or mannose receptor on dendritic cells lead to proper antigen presentation but do not enhance indirect allorecognition via HLA-DR.

Neutrophils efficiently cross-prime naive T cells in vivo

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2965-2973 ◽  
Author(s):  
Céline Beauvillain ◽  
Yves Delneste ◽  
Mari Scotet ◽  
Audrey Peres ◽  
Hugues Gascan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cross Presentation ◽  
Antigen Presenting

Abstract Neutrophils are professional phagocytes that migrate early, in high number, to the infection sites. Our study has analyzed how neutrophils cross-present antigens and influence CD8+ T-cell responses. By using highly purified neutrophils from peritoneal exudates and bone marrow, we have shown that neutrophils cross-present ovalbumin to a CD8+ T-cell hybridoma and to naive CD8+ T cells from OT1 transgenic mice. Cross-presentation by neutrophils was TAP and proteasome dependent and was as efficient as in macrophages. Moreover, it actually occurred earlier than in professional antigen-presenting cells. Peritoneal exudate neutrophils from mice injected intraperitoneally with ovalbumin also cross-presented ovalbumin, proving that neutrophils take up and present exogenous antigens into major histocompatibility complex I (MHC I) molecules in vivo. We then evaluated the in vivo influence of antigen cross-presentation by neutrophils on CD8+ T-cell response using β2-microglobulin-deficient mice transferred with OT1 CD8+ T cells and injected with ovalbumin-pulsed neutrophils. Four days after neutrophil injection, OT1 cells proliferated and expressed effector functions (IFN-γ production and cytolysis). They also responded efficiently to a rechallenge with ovalbumin-pulsed dendritic cells in CFA. These data are the first demonstration that neutrophils cross-prime CD8+ T cells in vivo and suggest that they may constitute, together with professional antigen-presenting cells, an attractive target to induce cytotoxic T cells in vaccines.

Robust Expansion of Cytomegalovirus (CMV) Antigen-Specific CD4+ and CD8+ T Cells Using Gene-Modified Activated T Cells as Antigen Presenting Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2384-2384
Author(s):  
J. Joseph Melenhorst ◽  
Scott R. Solomon ◽  
Stephan Mielke ◽  
Nancy F. Hensel ◽  
Austin J. Barrett
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
Fold Change ◽  
Antigen Specificity ◽  
Activated T Cells ◽  
Cell Numbers ◽  
Antigen Presenting

Abstract CMV reactivation after stem cell transplantation can be treated with CMV-specific T cells but current in vitro techniques using dendritic cells as antigen-presenting cells are time-consuming and expensive. To simplify the production of clinical grade CMV specific T cells, we evaluated gene-modified activated T cells (T-APC) as a reliable and easily produced source of APC to boost CD4 and CD8 T cell responses against the immunodominant CMV antigen pp65. Peripheral blood mononuclear cells from CMV seropositive donors were activated for 2–3 days in complete medium (IMDM, AB serum, glutamine, and antibiotics) supplemented with 0.8 mg/ml phytohaemagglutinin and 100 IU IL-2/ml. The cells were transduced with Phoenix-A derived recombinant virus encoding pp65 in retronectin-coated 6-well plates, and further expanded in anti-CD3 plus CD28-coated flasks for 3–7 more days. Cultured cells expressed high levels of HLA-DR, and the costimulatory molecules CD80 and CD86. Autologous PBMC (0.5 – 1.0 x 106 cells) were stimulated with 106 irradiated (25 Gy) transduced T-APC in a 24-well plate. After 1–3 days IL-2 and IL-7 were added to a final concentration of 20 IU/ml and 10 ng/ml, respectively. Two weeks later the T cell lines were tested for antigen specificity using the flow cytometric intracellular detection of interferon-gamma following stimulation for 6 hours with a pp65 peptide library of 15-mers, overlapping by 11 amino acids. This technique induced a 135-fold (median; range, 20–120,000) and a 255-fold (median; range, 17–20,000) expansion of pp65-specific CD4 and CD8 responder cells, respectively, in 10/10 seropositive donors (figure). To further improve proliferation, CD25-expressing T regulatory cells were removed from the PBMC at the start of the culture by immunomagnetic depletion (Miltenyi). In 7/10 donors, CD25 depletion resulted in increased CD4 and/or CD8 responder numbers (p>0.05; Mann Whitney paired t-test). Median increase in responder cell numbers was 4.25-fold (range, 1.4–6) for CD4+ T cells, and 4.2-fold (range, 3–7.5) for CD8+ T cells. These data indicate that T-APC efficiently boost pp65-specific CD4 and CD8 T cell numbers to clinically useful levels and that removal of CD25-expressing cells can further augment the total yield of antigen-specific T cells in most donors. The approach has the advantage of using a single leukocyte collection from the donor to generate large numbers of CMV-specific T cells within a total 3 week culture period using only one stimulation of antigen. Fold-change in the total number of pp-65 specific CD4 and CD8 T cells from PBMC Fold-change in the total number of pp-65 specific CD4 and CD8 T cells from PBMC

scholarly journals Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic–derived antigen-presenting cells

Blood ◽  
2012 ◽  
Vol 119 (16) ◽  
pp. 3844-3853 ◽  
Author(s):  
Tomomi Toubai ◽  
Isao Tawara ◽  
Yaping Sun ◽  
Chen Liu ◽  
Evelyn Nieves ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Data ◽  
Acute Gvhd ◽  
Antigen Presenting Cells ◽  
Cd8 T Cell ◽  
Donor T Cells ◽  
Antigen Presenting

Abstract It is currently thought that acute GVHD cannot be elicited in the absence of Ag presentation by radiosensitive host hematopoietic-derived APCs after allogeneic BM transplantation. Because clinical data suggest that sex-mismatched H-Y Ags may be important minor histocompatibility Ags for GVH responses, we directly tested their relevance and ability to initiate GVHD when presented by either the hematopoietic- (host or donor) or the nonhematopoietic-derived APCs. H-Y minor Ag incompatibility elicited both CD4+ and CD8+ T-cell driven GVHD lethality. Studies with various well-established BM chimera recipients, in contrast to the current views, have reported that in the absence of functional radiosensitive host hematopoietic-derived APCs, H-Y Ag presentation by either the donor hematopoietic-derived or the host nonhematopoietic-derived APCs is sufficient for inducing GVHD. Our data further suggest that infusion of sufficient numbers of alloreactive donor T cells will induce GVHD in the absence of radiosensitive host hematopoietic-derived APCs.

scholarly journals Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8+ T cells and dendritic cells

Blood ◽  
2013 ◽  
Vol 121 (26) ◽  
pp. 5184-5191 ◽  
Author(s):  
Catherine E. Terrell ◽  
Michael B. Jordan
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Physiological Mechanism ◽  
Cd8 T Cell ◽  
Key Points ◽  
Antigen Presenting

Key PointsDefects in perforin and related genes lead to abnormal T-cell activation and are associated with HLH. The physiological mechanism by which perforin protects from HLH involves CD8+ T-cell elimination of rare antigen-presenting dendritic cells.

scholarly journals Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells

Blood ◽  
2009 ◽  
Vol 113 (9) ◽  
pp. 2088-2095 ◽  
Author(s):  
Motoko Koyama ◽  
Daigo Hashimoto ◽  
Kazutoshi Aoyama ◽  
Ken-ichi Matsuoka ◽  
Kennosuke Karube ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Host Disease ◽  
Graft Versus Host ◽  
Alloreactive T Cells ◽  
Antigen Presenting

Dendritic cells (DCs) can be classified into 2 distinct subsets: conventional DCs (cDCs) and plasmacytoid DCs (pDCs). cDCs can prime antigen-specific T-cell immunity, whereas in vivo function of pDCs as antigen-presenting cells remains controversial. We evaluated the contribution of pDCs to allogeneic T-cell responses in vivo in mouse models of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation by an add-back study of MHC-expressing pDCs into major histocompatibility complex-deficient mice that were resistant to GVHD. Alloantigen expression on pDCs alone was sufficient to prime alloreactive T cells and cause GVHD. An inflammatory environment created by host irradiation has the decisive role in maturing pDCs for T-cell priming but this process does not require Toll-like receptor signaling. Thus, functional outcomes of pDC–T-cell interactions depend on the immunologic context of encounter. To our knowledge, these results are the first to directly demonstrate an in vivo pathogenic role of pDCs as antigen-presenting cells in an antigen-specific T cell–mediated disease in the absence of other DC subsets and to provide important insight into developing strategies for tolerance induction in transplantation.

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