scholarly journals Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens

2010 ◽  
Vol 207 (6) ◽  
pp. 1247-1260 ◽  
Author(s):  
Sarah L. Jongbloed ◽  
Andrew J. Kassianos ◽  
Kylie J. McDonald ◽  
Georgina J. Clark ◽  
Xinsheng Ju ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Cytotoxic T Lymphocyte ◽  
Poly I:C ◽  
T Helper ◽  
T Helper 1 ◽  
Cell Responses ◽  
Polycytidylic Acid ◽  
Infected Cells ◽  
Lymphocyte Responses

The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141+ DC subset. CD141+ DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-β, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c+ DC subset. Polyinosine-polycytidylic acid (poly I:C)–activated CD141+ DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8+ cytotoxic T lymphocytes than poly I:C–activated CD1c+ DCs. Importantly, CD141+ DCs, but not CD1c+ DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141+ DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8α+ DC subset. The data demonstrate a role for CD141+ DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.

scholarly journals A Novel Bacterium-Like Particle-Based Vaccine Displaying the SUDV Glycoprotein Induces Potent Humoral and Cellular Immune Responses in Mice

Viruses ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1149
Author(s):  
Shengnan Xu ◽  
Cuicui Jiao ◽  
Hongli Jin ◽  
Wujian Li ◽  
Entao Li ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Surface Display ◽  
Neutralizing Antibody ◽  
Hemorrhagic Fever ◽  
Poly I:C ◽  
Cell Mediated Immunity ◽  
T Helper ◽  
T Helper 1 ◽  
Prophylactic Vaccination ◽  
Cellular Immune

Sudan virus (SUDV) causes severe lethal hemorrhagic fever in humans and nonhuman primates. The most effective and economical way to protect against Sudan ebolavirus disease is prophylactic vaccination. However, there are no licensed vaccines to prevent SUDV infections. In this study, a bacterium-like particle (BLP)-based vaccine displaying the extracellular domain of the SUDV glycoprotein (eGP) was developed based on a gram-positive enhancer matrix-protein anchor (GEM-PA) surface display system. Expression of the recombinant GEM-displayed eGP (eGP-PA-GEM) was verified by Western blotting and immunofluorescence assays. The SUDV BLPs (SBLPs), which were mixed with Montanide ISA 201VG plus Poly (I:C) combined adjuvant, could induce high SUDV GP-specific IgG titers of up to 1:40,960 and robust virus-neutralizing antibody titers reached 1:460. The SBLP also elicited T-helper 1 (Th1) and T-helper 2 (Th2) cell-mediated immunity. These data indicate that the SBLP subunit vaccine has the potential to be developed into a promising candidate vaccine against SUDV infections.

scholarly journals Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Junghwa Lee ◽  
Masao Hashimoto ◽  
Se Jin Im ◽  
Koichi Araki ◽  
Hyun-Tak Jin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
T Helper ◽  
T Helper 1 ◽  
Cell Responses ◽  
Serotype 5 ◽  
Lcmv Infection

ABSTRACT Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling. IMPORTANCE During viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization.

scholarly journals Differential Immunogenicity of Epstein-Barr Virus Latent-Cycle Proteins for Human CD4+ T-Helper 1 Responses

2001 ◽  
Vol 75 (18) ◽  
pp. 8649-8659 ◽  
Author(s):  
Ann Leen ◽  
Pauline Meij ◽  
Irina Redchenko ◽  
Jaap Middeldorp ◽  
Elisabeth Bloemena ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
T Helper ◽  
Antigen Specificity ◽  
T Helper 1 ◽  
Barr Virus ◽  
Cell Responses ◽  
Nuclear Antigens ◽  
Epstein Barr

ABSTRACT Human CD4+ T-helper 1 cell responses to Epstein-Barr virus (EBV) infection are likely to be important in the maintenance of virus-specific CD8+ memory and/or as antiviral effectors in their own right. The present work has used overlapping peptides as stimulators of gamma interferon release (i) to identify CD4+ epitopes within four EBV latent-cycle proteins, i.e., the nuclear antigens EBNA1 and EBNA3C and the latent membrane proteins LMP1 and LMP2, and (ii) to determine the frequency and magnitude of memory responses to these proteins in healthy virus carriers. Responses to EBNA1 and EBNA3C epitopes were detected in the majority of donors, and in the case of EBNA1, their antigen specificity was confirmed by in vitro reactivation and cloning of CD4+ T cells using protein-loaded dendritic cell stimulators. By contrast, responses to LMP1 and LMP2 epitopes were seen much less frequently. EBV latent-cycle proteins therefore display a marked hierarchy of immunodominance for CD4+ T-helper 1 cells (EBNA1, EBNA3C ≫ LMP1, LMP2) which is different from that identified for the same proteins with respect to CD8+-T-cell responses (EBNA3C > EBNA1 > LMP2 ≫ LMP1). Furthermore, the range of CD4+ memory T-cell frequencies in peripheral blood of healthy virus carriers was noticeably lower and narrower than the corresponding range of latent antigen-specific CD8+-T-cell frequencies.

scholarly journals The lung vascular filter as a site of immune induction for T cell responses to large embolic antigen

2009 ◽  
Vol 206 (12) ◽  
pp. 2823-2835 ◽  
Author(s):  
Monique A.M. Willart ◽  
Hendrik Jan de Heer ◽  
Hamida Hammad ◽  
Thomas Soullié ◽  
Kim Deswarte ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
Bloodborne Pathogens ◽  
Cell Responses ◽  
Liver Sinusoids ◽  
A Site ◽  
Lymphocyte Responses

The bloodstream is an important route of dissemination of invading pathogens. Most of the small bloodborne pathogens, like bacteria or viruses, are filtered by the spleen or liver sinusoids and presented to the immune system by dendritic cells (DCs) that probe these filters for the presence of foreign antigen (Ag). However, larger pathogens, like helminths or infectious emboli, that exceed 20 µm are mostly trapped in the vasculature of the lung. To determine if Ag trapped here can be presented to cells of the immune system, we used a model of venous embolism of large particulate Ag (in the form of ovalbumin [OVA]-coated Sepharose beads) in the lung vascular bed. We found that large Ags were presented and cross-presented to CD4 and CD8 T cells in the mediastinal lymph nodes (LNs) but not in the spleen or liver-draining LNs. Dividing T cells returned to the lungs, and a short-lived infiltrate consisting of T cells and DCs formed around trapped Ag. This infiltrate was increased when the Toll-like receptor 4 was stimulated and full DC maturation was induced by CD40 triggering. Under these conditions, OVA-specific cytotoxic T lymphocyte responses, as well as humoral immunity, were induced. The T cell response to embolic Ag was severely reduced in mice depleted of CD11chi cells or Ly6C/G+ cells but restored upon adoptive transfer of Ly6Chi monocytes. We conclude that the lung vascular filter represents a largely unexplored site of immune induction that traps large bloodborne Ags for presentation by monocyte-derived DCs.

scholarly journals T-cell response to bacterial agents

2011 ◽  
Vol 5 (09) ◽  
pp. 640-645 ◽  
Author(s):  
Mario Milco D'Elios ◽  
Marisa Benagiano ◽  
Chiara Della Bella ◽  
Amedeo Amedei
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Response ◽  
Th2 Cells ◽  
T Helper ◽  
T Helper 1 ◽  
Cell Responses ◽  
Genetic And Environmental Factors ◽  
Bacteria And Fungi ◽  
Antigen Presenting

T-cell responses are crucial for the outcome of any infection. The type of effector T-cell reaction is determined by a complex interaction of antigen-presenting cells with naive T cells and involves genetic and environmental factors, including the type of antigen, cytokines, chemokines, co-stimulatory molecules, and signalling cascades. The decision for the immune response to go in a certain direction is based not on one signal alone, but rather on many different elements acting both synergistically and antagonistically, and through feedback loops leading to activation or inhibition of T cells. In the course of evolution different types of T cells have developed, such as T helper 1 (Th1) cells, which protect against intracellular bacteria; Th2 cells, which play a role against parasites; and Th17 cells, which face extracellular bacteria and fungi

scholarly journals Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8α+ dendritic cells

2010 ◽  
Vol 207 (6) ◽  
pp. 1261-1271 ◽  
Author(s):  
Lionel Franz Poulin ◽  
Mariolina Salio ◽  
Emmanuel Griessinger ◽  
Fernando Anjos-Afonso ◽  
Ligia Craciun ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Poly I:C ◽  
Clinical Protocols ◽  
Cell Responses ◽  
Promising Target ◽  
Important Player ◽  
And Function

In mouse, a subset of dendritic cells (DCs) known as CD8α+ DCs has emerged as an important player in the regulation of T cell responses and a promising target in vaccination strategies. However, translation into clinical protocols has been hampered by the failure to identify CD8α+ DCs in humans. Here, we characterize a population of human DCs that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8α+ DCs in phenotype and function. We describe the presence of such cells in the spleens of humans and humanized mice and report on a protocol to generate them in vitro. Like mouse CD8α+ DCs, human DNGR-1+ BDCA3hi DCs express Necl2, CD207, BATF3, IRF8, and TLR3, but not CD11b, IRF4, TLR7, or (unlike CD8α+ DCs) TLR9. DNGR-1+ BDCA3hi DCs respond to poly I:C and agonists of TLR8, but not of TLR7, and produce interleukin (IL)-12 when given innate and T cell–derived signals. Notably, DNGR-1+ BDCA3+ DCs from in vitro cultures efficiently internalize material from dead cells and can cross-present exogenous antigens to CD8+ T cells upon treatment with poly I:C. The characterization of human DNGR-1+ BDCA3hi DCs and the ability to grow them in vitro opens the door for exploiting this subset in immunotherapy.

scholarly journals Death Ligand Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Inhibits Experimental Autoimmune Thyroiditis

Endocrinology ◽  
2005 ◽  
Vol 146 (11) ◽  
pp. 4721-4726 ◽  
Author(s):  
Su He Wang ◽  
Zhengyi Cao ◽  
Julie M. Wolf ◽  
Mary Van Antwerp ◽  
James R. Baker
Keyword(s):  
Autoimmune Thyroiditis ◽  
T Helper ◽  
Mononuclear Cell Infiltration ◽  
T Helper 1 ◽  
Experimental Autoimmune Thyroiditis ◽  
Cell Responses ◽  
Control Protein ◽  
Necrosis Factor ◽  
Experimental Autoimmune

The role of TNF-related apoptosis-inducing ligand (TRAIL) in autoimmune thyroiditis is unclear. We used experimental autoimmune thyroiditis to clarify the contribution of TRAIL to the development of autoimmune thyroiditis. CBA/J mice were immunized with murine thyroglobulin, and spleen cells from these mice were subsequently injected into irradiated recipient CBA/J mice. One week later, the recipient mice were treated with recombinant TRAIL or a control protein. Compared with control animals, TRAIL-treated mice developed a milder form of the disease with a significant decrease in mononuclear cell infiltration in the thyroid and less thyroid follicular destruction. Furthermore, the number of apoptotic thyrocytes and also thyroglobulin-specific T helper-1 cell responses in TRAIL-treated mice was lower than that in the control animals. This study suggests that exogenous TRAIL suppresses the development of autoimmune thyroiditis via altering the function of cells involved in the immune response. These findings may contribute toward a novel treatment autoimmune thyroiditis.

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