scholarly journals TIM4 expression by dendritic cells mediates uptake of tumor-associated antigens and anti-tumor responses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicoletta Caronni ◽  
Giulia Maria Piperno ◽  
Francesca Simoncello ◽  
Oriana Romano ◽  
Simone Vodret ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Antigens ◽  
Immune Surveillance ◽  
Normal Lung ◽  
Mouse Lung ◽  
Cross Presentation ◽  
Phosphatidylserine Receptor ◽  
Lung Adenocarcinomas

AbstractAcquisition of cell-associated tumor antigens by type 1 dendritic cells (cDC1) is essential to induce and sustain tumor specific CD8+ T cells via cross-presentation. Here we show that capture and engulfment of cell associated antigens by tissue resident lung cDC1 is inhibited during progression of mouse lung tumors. Mechanistically, loss of phagocytosis is linked to tumor-mediated downregulation of the phosphatidylserine receptor TIM4, that is highly expressed in normal lung resident cDC1. TIM4 receptor blockade and conditional cDC1 deletion impair activation of tumor specific CD8+ T cells and promote tumor progression. In human lung adenocarcinomas, TIM4 transcripts increase the prognostic value of a cDC1 signature and predict responses to PD-1 treatment. Thus, TIM4 on lung resident cDC1 contributes to immune surveillance and its expression is suppressed in advanced tumors.

scholarly journals WDFY4 is required for cross-presentation in response to viral and tumor antigens

Science ◽  
2018 ◽  
Vol 362 (6415) ◽  
pp. 694-699 ◽  
Author(s):  
Derek J. Theisen ◽  
Jesse T. Davidson ◽  
Carlos G. Briseño ◽  
Marco Gargaro ◽  
Elvin J. Lauron ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Antigens ◽  
Critical Role ◽  
Tumor Rejection ◽  
Interleukin 12 ◽  
Cross Presentation ◽  
Histocompatibility Complex ◽  
Crispr Screen

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain–containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3–/– mice, Wdfy4–/– mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3–/– mice, Wdfy4–/– mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.

scholarly journals Yeast-Derived Human Immunodeficiency Virus Type 1 p55gag Virus-Like Particles Activate Dendritic Cells (DCs) and Induce Perforin Expression in Gag-Specific CD8+ T Cells by Cross-Presentation of DCs

2003 ◽  
Vol 77 (19) ◽  
pp. 10250-10259 ◽  
Author(s):  
Yasuko Tsunetsugu-Yokota ◽  
Yuko Morikawa ◽  
Maya Isogai ◽  
Ai Kawana-Tachikawa ◽  
Takashi Odawara ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Interleukin 12 ◽  
Virus Like Particles ◽  
Cross Presentation ◽  
Immunodeficiency Virus ◽  
Dc Maturation

ABSTRACT To evaluate the immunogenicity of human immunodeficiency virus (HIV) type 1 p55 gag virus-like particles (VLPs) released by budding from yeast spheroplasts, we have analyzed the effects of yeast VLPs on monocyte-derived dendritic cells (DCs). Yeast VLPs were efficiently incorporated into DCs via both macropinocytosis and endocytosis mediated by mannose-recognizing receptors, but not the mannose receptor. The uptake of yeast VLPs induced DC maturation and enhanced cytokine production, notably, interleukin-12 p70. We showed that yeast membrane components may contribute to DC maturation partly through Toll-like receptor 2 signaling. Thus, Gag particles encapsulated by yeast membrane may have an advantage in stimulating Gag-specific immune responses. We found that yeast VLPs, but not the control yeast membrane fraction, were able to activate both CD4+ and CD8+ T cells of HIV-infected individuals. We tested the effect of cross-presentation of VLP by DCs in two subjects recruited into a long-term nonprogressor-slow progressor cohort. When yeast VLP-loaded DCs of these patients were cocultured with peripheral blood mononuclear cells for 7 days, approximately one-third of the Gag-specific CD8+ T cells were activated and became perforin positive. However, some of the Gag-specific CD8+ T cells appeared to be lost during in vitro culture, especially in a patient with a high virus load. Our results suggest that DCs loaded with yeast VLPs can activate Gag-specific memory CD8+ T cells to become effector cells in chronically HIV-infected individuals, but there still remain unresponsive Gag-specific T-cell populations in these patients.

537 Conventional type 1 dendritic cells and natural killer cells demonstrate strong correlation to T lymphocyte infiltration in cervical cancer tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A573-A573
Author(s):  
Anushka Dikshit ◽  
Xiao-jun Ma ◽  
Bingqing Zhang
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Strong Correlation ◽  
Tumor Antigens ◽  
Spatial Relationship ◽  
Conventional Type

BackgroundThe ability of T cells to mediate anti-tumor immunity has been harnessed to develop successful immunotherapies in recent years. Although direct presentation of tumor antigens by tumor cells plays an important role in the effector function of cytotoxic T lymphocytes (CTLs), cross-presentation by professional antigen presenting cells such as dendritic cells (DCs) is vital for priming naive CD8+ T cells and developing a sustainable cytotoxic response. Natural killer (NK) cells within the tumor microenvironment (TME) recruit a specific population of DCs called conventional type 1 DCs (cDC1s) into the TME by secreting chemokines such as CCL5 and XCL1. However, these cells are very low in abundance and are characterized by the expression of numerous markers, making their detection in the tissue context challenging.MethodsTherefore, to interrogate the presence of cDC1 and NK cells in the TME and reveal their spatial relationship we utilized the highly sensitive and specific RNAscope Multiplex Fluorescence in situ hybridization (ISH) assay. Probes for XCR1, THBD, CLEC9A, and CCR5 were used to identify cDC1 cells within 4 cervical cancer tumors. These tumors were then assessed for the presence of NK cells by using specific marker probes such as CD56 and NCR1 and chemokines XCL1 and CCL5. Finally, CTLs were visualized to determine if there is a correlation between the presence of cDC1 and NK cells and CTL infiltration within the cervical cancer tumors.ResultsOur results revealed a strong correlation between the presence of NK cells, cDC1 cells, and CTLs within 3 out of 4 cervical cancer samples. The NK cells showed expression of the chemokines XCL1 and CCL5, which are the ligands for XCR1 and CCR5 respectively, suggesting that the XCR1+/CCR5+ cDC1 cells may have been potentially recruited by these NK cells. Regions high in cDC1 and NK cells also showed significantly higher levels of CTL recruitment, as indicated by the presence of CD8+/IFNG+ T cells. Conversely, 1 of the 4 cervical cancer samples demonstrated relatively lower levels of NK cells which correlated with lower cDC1 cells and in turn lower CTL infiltration.ConclusionsIn conclusion, by utilizing the RNAscope Multiplex ISH assay we were able to identify and visualize the spatial relationship between NK cells, CTLs, and cDC1 cells, a rare subset of DC cells that excel at presenting tumor antigens to T cells. Using this technology, it is possible to spatially interrogate the TME and detect specialized immune cells when assessing response to immunotherapies.

scholarly journals Tumors and the danger model.

2002 ◽  
Vol 49 (2) ◽  
pp. 295-302 ◽  
Author(s):  
Dariusz W Kowalczyk
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Tumor Antigens ◽  
Critical Role ◽  
Immune Surveillance ◽  
Tumor Escape ◽  
Principal Mechanism

This article reviews the evidence for the danger model in the context of immune response to tumors and the insufficiency of the immune system to eliminate tumor growth. Despite their potential immunogenicity tumors do not induce significant immune responses which could destroy malignant cells. According to the danger model, the immune surveillance system fails to detect tumor antigens because transformed cells do not send any danger signals which could activate dendritic cells and initiate an immune response. Instead, tumor cells or antigen presenting cells turn off the responding T cells and induce tolerance. The studies reviewed herein based on model tumor antigens, recombinant viral vectors and detection of tumor specific T cells by MHC/peptide tetramers underscore the critical role of tumor antigen presentation and the context in which it occurs. They indicate that antigen presentation only by activated but not by cancer or resting dendritic cells is necessary for the induction of immune responses to tumor antigens. It becomes apparent that the inability of dendritic cells to become activated provides a biological niche for tumor escape from immune destruction and seems to be a principal mechanism for the failure of tumor immune surveillance.

scholarly journals Thioesterase PPT1 balances viral resistance and efficient T cell crosspriming in dendritic cells

2019 ◽  
Vol 216 (9) ◽  
pp. 2091-2112 ◽  
Author(s):  
Pengju Ou ◽  
Lifen Wen ◽  
Xiaoli Liu ◽  
Jiancheng Huang ◽  
Xiaoling Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Viral Resistance ◽  
Cross Presentation ◽  
Endosomal Acidification ◽  
Molecular Rheostat ◽  
Rapid Clearance ◽  
Vesicular Stomatitis ◽  
Palmitoyl Protein Thioesterase

Conventional type 1 dendritic cells (cDC1s) are inherently resistant to many viruses but, paradoxically, possess fewer acidic phagosomes that enable antigen retention and cross-presentation. We report that palmitoyl-protein thioesterase 1 (PPT1), which catabolizes lipid-modified proteins in neurons, is highly expressed in cDC1s. PPT1-deficient DCs are more susceptible to vesicular stomatitis virus (VSV) infection, and mice with PPT1 deficiency in cDC1s show impaired response to VSV. Conversely, PPT1-deficient cDC1s enhance the priming of naive CD8+ T cells into tissue-resident KLRG1+ effectors and memory T cells, resulting in rapid clearance of tumors and Listeria monocytogenes. Mechanistically, PPT1 protects steady state DCs from viruses by promoting antigen degradation and endosomal acidification via V-ATPase recruitment. After DC activation, immediate down-regulation of PPT1 is likely to facilitate efficient cross-presentation, production of costimulatory molecules and inflammatory cytokines. Thus, PPT1 acts as a molecular rheostat that allows cDC1s to crossprime efficiently without compromising viral resistance. These results suggest potential therapeutics to enhance cDC1-dependent crosspriming.

The Role of Human T-Lymphotropic Virus Type 1 (HTLV-1)-Infected Dendritic Cells in the Development of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

1999 ◽  
Vol 73 (6) ◽  
pp. 4575-4581 ◽  
Author(s):  
Masahiko Makino ◽  
Satoshi Shimokubo ◽  
Shin-Ichi Wakamatsu ◽  
Shuji Izumo ◽  
Masanori Baba
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Virus Type ◽  
Spastic Paraparesis ◽  
Tropical Spastic Paraparesis ◽  
Normal Donor ◽  
Dependent Manner ◽  
T Lymphotropic Virus

ABSTRACT The development of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is closely associated with the activation of T cells which are HTLV-1 specific but may cross-react with neural antigens (Ags). Immature dendritic cells (DCs), differentiated from normal donor monocytes by using recombinant granulocyte-macrophage colony-stimulating factor and recombinant interleukin-4, were pulsed with HTLV-1 in vitro. The pulsed DCs contained HTLV-1 proviral DNA and expressed HTLV-1 Gag Ag on their surface 6 days after infection. The DCs matured by lipopolysaccharides stimulated autologous CD4+ T cells and CD8+ T cells in a viral dose-dependent manner. However, the proliferation level of CD4+ T cells was five- to sixfold higher than that of CD8+ T cells. In contrast to virus-infected DCs, DCs pulsed with heat-inactivated virions activated only CD4+ T cells. To clarify the role of DCs in HAM/TSP development, monocytes from patients were cultured for 4 days in the presence of the cytokines. The expression of CD86 Ag on DCs was higher and that of CD1a Ag was more down-regulated than in DCs generated from normal monocytes. DCs from two of five patients expressed HTLV-1 Gag Ag. Furthermore, both CD4+ and CD8+ T cells from the patients were greatly stimulated by contact with autologous DCs pulsed with inactivated viral Ag as well as HTLV-1-infected DCs. These results suggest that DCs are susceptible to HTLV-1 infection and that their cognate interaction with T cells may contribute to the development of HAM/TSP.

scholarly journals In Vivo Role of Dendritic Cells in a Murine Model of Pulmonary Cryptococcosis

2006 ◽  
Vol 74 (7) ◽  
pp. 3817-3824 ◽  
Author(s):  
Karen L. Wozniak ◽  
Jatin M. Vyas ◽  
Stuart M. Levitz
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
Mouse Lung

ABSTRACT Dendritic cells (DC) have been shown to phagocytose and kill Cryptococcus neoformans in vitro and are believed to be important for inducing protective immunity against this organism. Exposure to C. neoformans occurs mainly by inhalation, and in this study we examined the in vivo interactions of C. neoformans with DC in the lung. Fluorescently labeled live C. neoformans and heat-killed C. neoformans were administered intranasally to C57BL/6 mice. At specific times postinoculation, mice were sacrificed, and lungs were removed. Single-cell suspensions of lung cells were prepared, stained, and analyzed by microscopy and flow cytometry. Within 2 h postinoculation, fluorescently labeled C. neoformans had been internalized by DC, macrophages, and neutrophils in the mouse lung. Additionally, lung DC from mice infected for 7 days showed increased expression of the maturation markers CD80, CD86, and major histocompatibility complex class II. Finally, ex vivo incubation of lung DC from infected mice with Cryptococcus-specific T cells resulted in increased interleukin-2 production compared to the production by DC from naïve mice, suggesting that there was antigen-specific T-cell activation. This study demonstrated that DC in the lung are capable of phagocytosing Cryptococcus in vivo and presenting antigen to C. neoformans-specific T cells ex vivo, suggesting that these cells have roles in innate and adaptive pulmonary defenses against cryptococcosis.

scholarly journals Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells

2002 ◽  
Vol 76 (15) ◽  
pp. 7812-7821 ◽  
Author(s):  
Rogier W. Sanders ◽  
Esther C. de Jong ◽  
Christopher E. Baldwin ◽  
Joost H. N. Schuitemaker ◽  
Martien L. Kapsenberg ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Dendritic Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Virus Transmission ◽  
Viral Envelope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Dendritic cells (DC) support human immunodeficiency virus type 1 (HIV-1) transmission by capture of the virus particle in the mucosa and subsequent transport to the draining lymph node, where HIV-1 is presented to CD4+ Th cells. Virus transmission involves a high-affinity interaction between the DC-specific surface molecule DC-SIGN and the viral envelope glycoprotein gp120 and subsequent internalization of the virus, which remains infectious. The mechanism of viral transmission from DC to T cells is currently unknown. Sentinel immature DC (iDC) develop into Th1-promoting effector DC1 or Th2-promoting DC2, depending on the activation signals. We studied the ability of these effector DC subsets to support HIV-1 transmission in vitro. Compared with iDC, virus transmission is greatly upregulated for the DC1 subset, whereas DC2 cells are inactive. Increased transmission by DC1 correlates with increased expression of ICAM-1, and blocking studies confirm that ICAM-1 expression on DC is important for HIV transmission. The ICAM-1-LFA-1 interaction is known to be important for immunological cross talk between DC and T cells, and our results indicate that this cell-cell contact is exploited by HIV-1 for efficient transmission.

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