Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

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Human Dendritic Cells: Ontogeny and Their Subsets in Health and Disease

Medical Sciences ◽

10.3390/medsci6040088 ◽

2018 ◽

Vol 6 (4) ◽

pp. 88 ◽

Cited By ~ 8

Author(s):

Sandra Solano-Gálvez ◽

Sonia Tovar-Torres ◽

María Tron-Gómez ◽

Ariane Weiser-Smeke ◽

Diego Álvarez-Hernández ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Immune Responses ◽

Cd8 T Cells ◽

Current Knowledge ◽

Lymphoid Organ ◽

Heterogeneous Population ◽

Health And Disease ◽

Human Dendritic Cells ◽

Activation Status

Dendritic cells (DCs) are a type of cells derived from bone marrow that represent 1% or less of the total hematopoietic cells of any lymphoid organ or of the total cell count of the blood or epithelia. Dendritic cells comprise a heterogeneous population of cells localized in different tissues where they act as sentinels continuously capturing antigens to present them to T cells. Dendritic cells are uniquely capable of attracting and activating naïve CD4+ and CD8+ T cells to initiate and modulate primary immune responses. They have the ability to coordinate tolerance or immunity depending on their activation status, which is why they are also considered as the orchestrating cells of the immune response. The purpose of this review is to provide a general overview of the current knowledge on ontogeny and subsets of human dendritic cells as well as their function and different biological roles.

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303 Systemic Control of Plasmacytoid Dendritic Cells By CD8+ T Cells and Commensal Microbiota

Gastroenterology ◽

10.1016/s0016-5085(08)60206-1 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-43

Author(s):

Daisuke Fujiwara ◽

Bo Wei ◽

Laura L. Presley ◽

Sarah N. Brewer ◽

Michael McPherson ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Plasmacytoid Dendritic Cells ◽

Commensal Microbiota ◽

Systemic Control

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Compensatory roles of CD8+ T cells and plasmacytoid dendritic cells in gut immune regulation for reduced function of CD4+ Tregs

Oncotarget ◽

10.18632/oncotarget.7510 ◽

2016 ◽

Vol 7 (10) ◽

pp. 10947-10961 ◽

Cited By ~ 2

Author(s):

Young-In Kim ◽

Bo-Ra Lee ◽

Jae-Hee Cheon ◽

Bo-Eun Kwon ◽

Mi-Na Kweon ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Immune Regulation ◽

Plasmacytoid Dendritic Cells

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Faculty Opinions recommendation of Systemic control of plasmacytoid dendritic cells by CD8+ T cells and commensal microbiota.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1107088.563068 ◽

2008 ◽

Author(s):

Eckhard Podack

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Plasmacytoid Dendritic Cells ◽

Commensal Microbiota ◽

Systemic Control

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T Cell Responses in Patients Vaccinated with Telomerase (hTERT)-mRNA Transfected Dendritic Cells.

Blood ◽

10.1182/blood.v114.22.373.373 ◽

2009 ◽

Vol 114 (22) ◽

pp. 373-373

Author(s):

Else Marit Inderberg Suso ◽

Anne-Marie Rasmussen ◽

Steinar Aamdal ◽

Svein Dueland ◽

Gustav Gaudernack ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Patients ◽

Cd8 T Cells ◽

Stable Disease ◽

T Cell Responses ◽

Htert Mrna ◽

Cell Responses

Abstract Abstract 373 Two cancer patients were vaccinated with dendritic cells (DC) loaded with telomerase (hTERT) mRNA to investigate the safety, tolerability and immunological response to vaccination prior to the start of a new phase I/II clinical trial. Following written informed consent one primary lung adenocarcinoma with metastasis and one patient with a relapsed pancreatic ductal type of adenocarcinoma, were treated with autologus monocyte-derived DC transfected with mRNA encoding hTERT. The patients first received four weekly injections administered intradermally followed by monthly booster injections. Peripheral blood mononuclear cells (PBMC) at each vaccination time point were tested in vitro with transfected DC and a panel of 24 overlapping hTERT peptides. In addition, hTERT-specific CD8+ T cells were monitored by pentamer staining. The treatment was well tolerated with minor side effects. Immune responses against telomerase-transfected DC and some of the overlapping hTERT peptides were detected in both patients. We also detected hTERT-specific CD8+ T cells in both patients by pentamer staining in post-vaccination samples. The lung cancer patients obtained a stable disease that lasted 18 months while the patient with pancreas cancer who started the DC vaccination in July 2007 following palliative chemotherapy, still is in stable disease by continuously boost vaccination. T-cell responses against telomerase epitopes have also been identified in both non-vaccinated cancer patients and cancer patients previously vaccinated with telomerase peptide. Since patients with these findings often show extraordinary clinical courses of their disease we hypothesize that it exists a high degree of immunogenicity and HLA promiscuity for some telomerase epitopes. In this study we have shown that vaccination with hTERT-mRNA transfected DC is safe and able to induce robust immune responses to several telomerase T-cell epitopes both in CD4+ and CD8+ T cells. This opens up the possibility for a broad clinical application of mRNA hTERT DC vaccines. Furthermore, responding T cells identified in these patients are strong candidates for T-cell receptor cloning and the receptors identified can thereafter be transferred into T cells creating the next generation of immuno-gene therapy with retargeted T cells. Disclosures: No relevant conflicts of interest to declare.

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Low Blood Counts of Memory/Effector CD8 T Cells, Gamma/Delta T Cells, Memory B Cells and Plasmacytoid Dendritic Cells and High Counts of Th2 Cells in Systemic Sclerosis

Blood ◽

10.1182/blood.v118.21.4917.4917 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4917-4917

Author(s):

Jan Storek ◽

Rob Woolson ◽

Paul K. Wallace ◽

Gregory Sempowski ◽

Peter A. McSweeney ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Systemic Sclerosis ◽

B Cells ◽

Cd8 T Cells ◽

Plasmacytoid Dendritic Cells ◽

Memory B Cells ◽

Gamma Delta T Cells ◽

Gamma Delta ◽

Memory Cd8 T Cells

Abstract Abstract 4917 Introduction: Systemic sclerosis (SSc) is presumed to result from aberrant activation of autoreactive T cells. However, the exact pathogenesis of SSc is not known. Patients and Methods: To contribute to the understanding of the immunopathology of systemic sclerosis (SSc), we compared blood counts of multiple lymphocyte subsets between 20 adult SSc patients not treated with immunomodulatory drugs and healthy controls. The patients had to fit entry criteria for SCOT trial (Scleroderma – Cyclophosphamide or Transplantation?, www.sclerodermatrial.org), i.e, 1. symptoms for no longer than 5 years (except for Raynaud's phenomenon), 2. diffuse scleroderma, and 3. either moderate lung involvement (forced vital capacity (FVC) or diffusion of carbon monoxide (DLCO) between 45 and 70% predicted) or moderate kidney involvement (history of hypertensive renal crisis, but normal renal function at study entry). Multiparameter flow cytometry was used for the determination of the lymphocyte subset counts. Results: Counts of the following subsets were significantly lower in the patients compared to the controls: total T cells (median 1316 vs 2088/ul, p=0.015), total CD8 T cells (273 vs 580/ul, p<0.001), central memory CD8 T cells (23 vs 87/ul, p<0.001), effector memory CD8 T cells (17 vs 39/ul, p=0.015), effector CD8 T cells (28 vs 68/ul, p=0.001), gamma/delta T cells (31 vs 77/ul, p<0.001), switched (IgM/DàIgG/A isotype switched) memory B cells (6 vs 26/ul, p<0.001), non-switched memory B cells (7 vs 17/ul, p=0.004), and plasmacytoid dendritic cells (2 vs 6/ul, p=0.002). Counts of Th2-biased (producing interleukin-4 upon polyclonal stimulation) CD4 as well as CD8 T cells were significantly higher in the patients compared to the controls (248 vs 139/ul for CD4, p=0.002, and 259 vs 164/ul for CD8, p<0.001). Conclusion: Immunopathology of SSc is complex. Low blood counts of memory/effector CD8 T cells, gamma/delta T cells, memory B cells and plasmacytoid dendritic cells and Th2-biased T cells may play a role in the pathogenesis of SSc. However, cause and effect relations need to be established. Given previous reports of increased numbers of CD8 and gamma/delta T cells in the affected tissues of patients with systemic sclerosis and increased numbers of plasmacytoid dendritic cells in the affected tissues of patients with autoimmune diseases (compared to healthy individuals) (Prescott RJ et al: J Pathol 166 (1992) 255–63, Atamas SP et al: Arthritis Rheum 42 (1999) 1168–78, Giacomelli R et al: Arthritis Rheum 41 (1998) 327–34, Yurovski VV et al: J Immunol 153 (1994) 881–91, Nestle FO et al: J Exp Med 202 (2005) 35–43, Farkas L et al: Am J Pathol 159 (2001) 237–43), it is possible that the low blood counts of CD8 T cells, gamma/delta T cells and plasmacytoid dendritic cells result from redistribution of these cells from blood to affected tissues. Disclosures: No relevant conflicts of interest to declare.

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Human plasmacytoid dendritic cells efficiently cross-present exogenous Ags to CD8+ T cells despite lower Ag uptake than myeloid dendritic cell subsets

Blood ◽

10.1182/blood-2012-06-435644 ◽

2013 ◽

Vol 121 (3) ◽

pp. 459-467 ◽

Cited By ~ 97

Author(s):

Jurjen Tel ◽

Gerty Schreibelt ◽

Simone P. Sittig ◽

Till S. M. Mathan ◽

Sonja I. Buschow ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Human Peripheral Blood ◽

Adaptive Immune System ◽

Plasmacytoid Dendritic Cells ◽

Cell Responses ◽

Adaptive Immune ◽

Antitumor Immunotherapy

Abstract In human peripheral blood, 4 populations of dendritic cells (DCs) can be distinguished, plasmacytoid dendritic cells (pDCs) and CD16+, CD1c+, and BDCA-3+ myeloid DCs (mDCs), each with distinct functional characteristics. DCs have the unique capacity to cross-present exogenously encountered antigens (Ags) to CD8+ T cells. Here we studied the ability of all 4 blood DC subsets to take up, process, and present tumor Ags to T cells. Although pDCs take up less Ags than CD1c+ and BDCA3+ mDCs, pDCs induce potent Ag-specific CD4+ and CD8+ T-cell responses. We show that pDCs can preserve Ags for prolonged periods of time and on stimulation show strong induction of both MHC class I and II, which explains their efficient activation of both CD4+ and CD8+ T cells. Furthermore, pDCs cross-present soluble and cell-associated tumor Ags to cytotoxic T lymphocytes equally well as BDCA3+ mDCs. These findings, and the fact that pDCs outnumber BDCA3+ mDCs, both in peripheral blood and lymph nodes, together with their potent IFN-I production, known to activate both components of the innate and adaptive immune system, put human pDCs forward as potent activators of CD8+ T cells in antitumor responses. Our findings may therefore have important consequences for the development of antitumor immunotherapy.

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