Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR - PubMed (original) (raw)

. 2010 Sep 9;116(10):1685-97.

doi: 10.1182/blood-2010-01-264960. Epub 2010 Jun 7.

Anne-Laure Flamar, Yanying Cao, Jean-Philippe Blanck, Maochang Liu, Amy O'Bar, Olivier Agouna-Deciat, Peter Klucar, Luann Thompson-Snipes, Sandra Zurawski, Yoram Reiter, A Karolina Palucka, Gerard Zurawski, Jacques Banchereau

Affiliations

Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR

Eynav Klechevsky et al. Blood. 2010.

Abstract

We evaluated human CD8(+) T-cell responses generated by targeting antigens to dendritic cells (DCs) through various lectin receptors. We found the immunoreceptor tyrosine-based inhibitory motif-containing DC immunoreceptor (DCIR) to mediate potent cross-presentation. A single exposure to a low dose of anti-DCIR-antigen conjugate initiated antigen-specific CD8(+) T-cell immunity by all human DC subsets including ex vivo-generated DCs, skin-isolated Langerhans cells, and blood myeloid DCs and plasmacytoid DCs. The delivery of influenza matrix protein (FluMP) through DCIR resulted in expansion of FluMP-specific memory CD8(+) T cells. Enhanced specific CD8(+) T-cell responses were observed when an antigen was delivered to the DCs via DCIR, compared with those induced by a free antigen, or antigen conjugated to a control monoclonal antibody or delivered via DC-SIGN, another lectin receptor. DCIR targeting also induced primary CD8(+) T-cell responses against self (MART-1) and viral (HIV gag) antigens. Addition of Toll-like receptor (TLR) 7/8 agonist enhanced DCIR-mediated cross-presentation as well as cross-priming, particularly when combined with a CD40 signal. TLR7/8 activation was associated with increased expansion of the primed CD8(+) T cells, high production of interferon-γ and tumor necrosis factor-α, and reduced levels of type 2-associated cytokines. Thus, antigen targeting via the human DCIR receptor allows activation of specific CD8(+) T-cell immunity.

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Figures

Figure 1

Figure 1

Cellular distribution of DCIR. (A) Flow cytometry analysis of DCIR expression on peripheral blood mononuclear cells. Circulating mononuclear cells were stained with 10 μg/mL anti-DCIR mAb followed by phycoerythrin-conjugated goat anti–mouse IgG. Cells were incubated with anti-CD19, anti-CD4, anti-CD8 (for lymphocytes), anti-CD16, anti-CD56 (for NK cells) not shown, anti-CD14 mAb (for monocytes), or with anti-CD11c, anti–HLA-DR, and anti-CD123 mAb (for pDCs or mDCs) and analyzed by flow cytometry. Data are representative of 3 independent experiments performed on 3 different donors. (B) Expression analysis of DCIR by flow cytometry on skin-derived DC subsets: epidermal LCs, dermal CD1a+ DCs, and dermal CD14+ DCs. (C) Human epidermal sheets, stained with anti-DCIR and analyzed by fluorescence microscopy, revealed the expression of DCIR on HLA-DR+ LCs. Image was captured using an Olympus BX51 microscope with Planapo 40×/0.95 dry objective, Photometrics Coolsnap HQ camera, and Metamorph software Version 6.2r6. Channel separation was done in Adobe Photoshop CS. (D) Expression analysis of DCIR by flow cytometry on CD34+-derived DC subsets CD1a+ LCs and CD14+ DCs.

Figure 2

Figure 2

Engineering and characterization of targeted proteins into DCIR mAb. (A) Five constructs are shown. (I) Diagram of mouse IgG1 cross-linked to the target antigen FluMP. (II-III) Diagram of chimeric mAbs (IgG4).doc conjugated to coh.antigen (FluMP [II] or MART-1 [III]). (IV-V) Diagram of chimeric fusion mAb IgG4-antigen (MART-1 [IV] or HIV gag p24 [V]). (B) Staining of HLA-A201–FluMP complexes on CD34+-derived DCs unpulsed (control DCs, gray histogram), or pulsed with 50nM DCIR-targeted FluMP. Cells were activated with 5 μg/mL anti-CD40 mAb (12E12, Baylor Research Institute; BIIR) and stained after 24 hours with phycoerythrin-labeled tetramerized anti–HLA-A201–FluMP Fab (M1D12). (C) Cross-presentation of FluMP to CD8+ T cells by autologous HLA-A201+CD34+–derived LCs that were cultured with 8nM (top panel) or 0.8nM (bottom panel) of anti–DCIR.doc-coh.FluMP or IgG4.doc-coh.FluMP conjugate mAbs. Dot plots show the proportions of HLA-A201–FluMP(58-66) peptide tetramer-positive CD8+ T cells after 10 days. (D) Proportions of HLA-A201–FluMP(58-66) tetramer-positive CD8+ T cells induced by DCs that were pulsed for 18 hours with 8nM anti–DCIR.doc-coh.FluMP or control IgG2a.doc-coh.FluMP conjugate mAbs, washed and cultured with autologous CD8+ T cells for 10 days. Graphs show the proportions of HLA-A201–FluMP(58-66) tetramer-positive CD8+ T cells, mean ± SD; n = 3.

Figure 3

Figure 3

DCIR allows cross-presentation of proteins by LCs. (A) Skin-derived LCs from an HLA-A201+ donor were targeted with 8nM each of anti-DC.doc-coh.FluMP, IgG4.doc-coh.FluMP conjugate mAbs, or free FluMP matured with CD40L, and cocultured with autologous CD8+ T cells. Ten days later, CD8+ T-cell expansion was evaluated by specific HLA-A201–FluMP(58-66) tetramer staining. Data are representative of 2 independent experiments performed with cells from 2 different donors. (B) IFN-γ levels as measured by Luminex in the culture supernatant of CD8+ T cells expanded for 10 days by autologous skin LCs targeted with anti–DCIR.doc-coh.FluMP or IgG4.doc-coh.FluMP conjugate mAbs. Graph represents mean ± SD; n = 3.

Figure 4

Figure 4

DCIR is a global target for all blood DC subsets. (A) Blood-derived mDCs from an HLA-A201+ donor are targeted with 8nM, 0.8nM, or 80pM each anti–DCIR.doc-coh.FluMP (clone 24A5), IgG4.doc-coh.FluMP conjugate mAbs, or free coh.FluMP, matured with CD40L and cocultured with autologous CD8+ T cells. Ten days later, CD8+ T-cell expansion was evaluated by specific HLA-A201–FluMP(58-66) tetramer staining. Data are representative of 3 independent experiments. (B) Blood-derived pDCs from an HLA-A201+ donor were targeted with 8nM, 0.8nM, or 80pM each anti–DCIR.doc-coh.FluMP (clone 24A5), IgG4.doc-coh.FluMP, or free coh.FluMP, matured with CD40L and cocultured with autologous CD8+ T cells. Ten days later, T-cell expansion was evaluated by specific HLA-A201–FluMP(58-66) tetramer staining. Data are representative of 3 independent experiments. (C) Percentage of FluMP-specific CD8+ T cells induced by 8nM DCIR.doc-coh.FluMP complex mAb-targeted mDCs or pDCs. Graph represents results of 3 independent experiments using 2 different clones of DCIR mAb. P = .02.

Figure 5

Figure 5

Cross-priming of Mart-1 and HIV gag p24 protein by anti-DCIR fusion mAb. (A) Skin-derived LCs from an HLA-A201+ donor were purified and cultured for 10 days with autologous purified T cells in the presence of 30nM anti–DCIR.doc-coh.MART-1 or IgG4.doc-coh.MART-1 conjugate mAbs. DCs were activated with CD40L. MART-1–specific CD8+ T-cell expansion was measured with a specific HLA-A201-MART-1(26-35) tetramer. (B) Anti–DCIR-MART-1 or IgG4-MART-1 (25nM) fusion proteins were used to target monocyte-derived IFN-α DCs. DCs were activated with CD40L and cultured with naive autologous CD8+ T cells. After 10 days, cells were restimulated for 24 hours with fresh DCs loaded with peptides derived from MART-1 protein or with unloaded DCs as a control. Plot shows the percentage of primed CD8+ T cells coexpressing IFN-γ and CD107a in response to a specific MART-1 peptide cluster. (C) CD34+-derived LCs were targeted with DCIR-MART-1 or control IgG4-MART-1 fusion proteins and cultured with naive CD8+ T cells for 9 days. Graph represents the percentage of cells coexpressing Granzyme B and perforin as analyzed at the end of the culture by flow cytometry. Values in the graph are the average of triplicates ± SD. Data are representative of 2 independent experiments. (D) Anti–DCIR-p24 or control IgG4-p24 (25nM) fusion proteins were used to target CD34+-derived LCs. DCs were activated with CD40L and cultured with naive autologous CD8+ T cells. After 2 consecutive stimulations, the proliferated cells were sorted and restimulated for 24 hours with fresh LCs and HIV gag p24 protein to evaluate IFN-γ secretion by Luminex. Cells with no protein served as a control. Values are average of duplicates. Data are representative of 2 independent experiments.

Figure 6

Figure 6

TLR7/8-signaling enhances DCIR-mediated secondary CD8+ T-cell response by mDCs. (A) Blood-derived mDCs from an HLA-A201+ donor were targeted with 12nM, 2nM, or 200pM of anti–DCIR.doc-coh.FluMP complex mAb, activated with either TLR3, TLR4, or TLR7/8 agonists (poly I:C, LPS, or CL075) and cocultured with autologous CD8+ T cells for 10 days. Graph represents the percentage of FluMP-specific CD8+ T cells measured with a specific HLA-A201–FluMP(58-66) tetramer for each amount of anti–DCIR.doc-coh.FluMP complex mAb and with each DC-activator tested. DCs with no activation were used as a control: no activation (—), TLR7/8 (♦), TLR3 (*), and TLR4 (○) agonists; CL075, poly I:C, and LPS, respectively. Data are representative of 4 independent experiments with 4 different donors. The graph represents mean ± SD; n = 3. (B) Blood-derived mDCs from an HLA-A201+ donor were targeted with 8nM anti–DCIR.doc-coh.FluMP or IgG4.doc-coh.FluMP complex mAb, activated with TLR7/8, TLR3, and TLR4 agonists (CL075, poly I:C, and LPS, respectively) and cocultured with autologous CD8+ T cells for 10 days. Graph represents the percentage of FluMP-specific CD8+ T cells as measured with a specific HLA-A201–FluMP(58-66) tetramer. Conditions indicated in the graph are as follows: no activation, CL075 1μg/mL; poly I:C, 10 μg/mL; and LPS, 50 ng/mL. The graph represents mean ± SD; n = 3. (C) Same experiment as in panel B. Graph represents the mean percentage of FluMP-specific CD8+ T cells as measured with a specific HLA-A201–FluMP(58-66) tetramer. Conditions indicated in the graph are as follows: no activation; CL075-0.2μg/mL and 2 μg/mL; poly I:C, 5 μg/mL and 25 μg/mL; LPS, 10 ng/mL and 100 ng/mL.

Figure 7

Figure 7

TLR7/8-signaling enhances DCIR-mediated primary CD8+ T-cell response by mDCs. (A) Blood-derived mDCs from an HLA-A201+ donor were targeted with 17nM of anti–DCIR-MART-1 or a control IgG4-MART-1 fusion proteins, activated with CD40L (100 ng/mL), CL075 (1 μg/mL), poly I:C (5 μg/mL), or LPS (50 ng/mL) and cocultured with autologous naive CD8+ T cells for 10 days. The expansion of MART-1–specific CD8+ T cells was measured with a specific HLA-A201-MART-1(26-35) tetramer. Data are of 2 independent experiments with 2 different donors. (B) Blood-derived mDCs from an HLA-A201+ donor were targeted with 30nM of anti–DCIR-MART-1 fusion protein or anti–DCIR-p24, activated with either CD40L or TLR7/8 agonists, and cocultured with autologous naive CD8+ T cells for 10 days. (Top panel) The proportions of HLA-A201-MART-1(26-35) peptide tetramer-positive CD8+ T cells expanded by purified blood mDCs cultured with anti–DCIR-MART-1 fusion protein and activated with either CD40L or TLR7/8 agonist. (Bottom panel) The proportions of HLA-A201-HIV gag p24(151-159) peptide tetramer-positive CD8+ T cells expanded by purified blood mDCs targeted with anti–DCIR-p24 fusion protein and activated with either CD40L or TLR7/8 agonist. Data are of 2 independent experiments with 2 different donors. (C) The expression of intracellular effector molecules Granzyme B and perforin was assessed by flow cytometry on CD8+ T cells primed by IFN-α DCs targeted with 10nM of anti–DCIR-MART-1 or IgG4-MART-1 fusion proteins and activated with CD40L, CL075, or a combination of CD40L and CL075. The expression on the antigen specific MART-1(26-35)-positive cells was analyzed by co staining with the corresponding HLA-A201-tetramer. Data are representative of 2 independent experiments. (D) The frequency of MART-1–specific CD8+ T cells, as measured with a specific HLA-A201-MART-1(26-35) tetramer, after expansion with anti–DCIR-MART-1–targeted DCs that were activated with CD40L, TLR7/8 ligand, or a combination of CD40L and TLR7/8 ligand. IgG4-MART-1 fusion protein or no antigen conditions served as controls. Each dot represents a single experiment. (E top panel) IFN-α DCs were targeted with 17nM of anti–DCIR-MART-1 or a control IgG4-MART-1 fusion proteins, activated with CD40L (100 ng/mL), CL075 (1 μg/mL), poly I:C (10 μg/mL), or LPS (50 ng/mL) and cocultured with autologous naive CD8+ T cells. Ten days later, cells were restimulated with fresh DCs that were loaded with 15mer overlapping peptides derived from the MART-1 protein. Plots show the level of intracytoplasmic IFN-γ by CD8+ T cells after 5-hour stimulation in the presence of monensin. Data are representative of 3 independent experiments. (Bottom panel) Anti–DCIR-p24 or a control IgG4-p24 fusion proteins were used as a model antigen. (F) IFN-α DCs were targeted with 113nM anti–DCIR-MART-1 fusion protein activated with either CD40L (100 ng/mL) or CL075 (1 μg/mL) and cocultured with autologous naive CD8+ T cells. Ten days later, cells were restimulated with fresh DCs that were loaded with 15mer overlapping peptides derived from the MART-1 protein. The levels of IL-4, IL-5, IL-13, IFN-γ, TNF-α, and IL-12p40 were measured by Luminex in the culture supernatant after 24 hours. The graph represents mean ± SD; n = 3. (G) IFN-α DCs were targeted with 10nM anti–DCIR-MART-1 (▴) or a control IgG4-MART-1 (formula image) fusion proteins activated with either CD40L (100 ng/mL) or CL075 (1 μg/mL), or a combination of CD40L and CL075 and cocultured with autologous naive CD8+ T cells. Coculture in the absence of an antigen served as an additional control (□). Ten days later, cells were restimulated with fresh IFN-α DCs that were loaded with MART-1 fusion protein and analyzed by flow cytometry for their intracellular cytokine production. Graphs show the frequency of IFN-γ (left panel) and IFN-γ+TNF-α+ (right panel) producing CD8+ T cells primed by DCIR-targeted, or control IFN-α DCs after 5-hour restimulation in the presence of monensin and 0.25 μg/mL of anti-CD28/CD49d mAb (n = 3).

Figure 7

Figure 7

TLR7/8-signaling enhances DCIR-mediated primary CD8+ T-cell response by mDCs. (A) Blood-derived mDCs from an HLA-A201+ donor were targeted with 17nM of anti–DCIR-MART-1 or a control IgG4-MART-1 fusion proteins, activated with CD40L (100 ng/mL), CL075 (1 μg/mL), poly I:C (5 μg/mL), or LPS (50 ng/mL) and cocultured with autologous naive CD8+ T cells for 10 days. The expansion of MART-1–specific CD8+ T cells was measured with a specific HLA-A201-MART-1(26-35) tetramer. Data are of 2 independent experiments with 2 different donors. (B) Blood-derived mDCs from an HLA-A201+ donor were targeted with 30nM of anti–DCIR-MART-1 fusion protein or anti–DCIR-p24, activated with either CD40L or TLR7/8 agonists, and cocultured with autologous naive CD8+ T cells for 10 days. (Top panel) The proportions of HLA-A201-MART-1(26-35) peptide tetramer-positive CD8+ T cells expanded by purified blood mDCs cultured with anti–DCIR-MART-1 fusion protein and activated with either CD40L or TLR7/8 agonist. (Bottom panel) The proportions of HLA-A201-HIV gag p24(151-159) peptide tetramer-positive CD8+ T cells expanded by purified blood mDCs targeted with anti–DCIR-p24 fusion protein and activated with either CD40L or TLR7/8 agonist. Data are of 2 independent experiments with 2 different donors. (C) The expression of intracellular effector molecules Granzyme B and perforin was assessed by flow cytometry on CD8+ T cells primed by IFN-α DCs targeted with 10nM of anti–DCIR-MART-1 or IgG4-MART-1 fusion proteins and activated with CD40L, CL075, or a combination of CD40L and CL075. The expression on the antigen specific MART-1(26-35)-positive cells was analyzed by co staining with the corresponding HLA-A201-tetramer. Data are representative of 2 independent experiments. (D) The frequency of MART-1–specific CD8+ T cells, as measured with a specific HLA-A201-MART-1(26-35) tetramer, after expansion with anti–DCIR-MART-1–targeted DCs that were activated with CD40L, TLR7/8 ligand, or a combination of CD40L and TLR7/8 ligand. IgG4-MART-1 fusion protein or no antigen conditions served as controls. Each dot represents a single experiment. (E top panel) IFN-α DCs were targeted with 17nM of anti–DCIR-MART-1 or a control IgG4-MART-1 fusion proteins, activated with CD40L (100 ng/mL), CL075 (1 μg/mL), poly I:C (10 μg/mL), or LPS (50 ng/mL) and cocultured with autologous naive CD8+ T cells. Ten days later, cells were restimulated with fresh DCs that were loaded with 15mer overlapping peptides derived from the MART-1 protein. Plots show the level of intracytoplasmic IFN-γ by CD8+ T cells after 5-hour stimulation in the presence of monensin. Data are representative of 3 independent experiments. (Bottom panel) Anti–DCIR-p24 or a control IgG4-p24 fusion proteins were used as a model antigen. (F) IFN-α DCs were targeted with 113nM anti–DCIR-MART-1 fusion protein activated with either CD40L (100 ng/mL) or CL075 (1 μg/mL) and cocultured with autologous naive CD8+ T cells. Ten days later, cells were restimulated with fresh DCs that were loaded with 15mer overlapping peptides derived from the MART-1 protein. The levels of IL-4, IL-5, IL-13, IFN-γ, TNF-α, and IL-12p40 were measured by Luminex in the culture supernatant after 24 hours. The graph represents mean ± SD; n = 3. (G) IFN-α DCs were targeted with 10nM anti–DCIR-MART-1 (▴) or a control IgG4-MART-1 (formula image) fusion proteins activated with either CD40L (100 ng/mL) or CL075 (1 μg/mL), or a combination of CD40L and CL075 and cocultured with autologous naive CD8+ T cells. Coculture in the absence of an antigen served as an additional control (□). Ten days later, cells were restimulated with fresh IFN-α DCs that were loaded with MART-1 fusion protein and analyzed by flow cytometry for their intracellular cytokine production. Graphs show the frequency of IFN-γ (left panel) and IFN-γ+TNF-α+ (right panel) producing CD8+ T cells primed by DCIR-targeted, or control IFN-α DCs after 5-hour restimulation in the presence of monensin and 0.25 μg/mL of anti-CD28/CD49d mAb (n = 3).

Figure 7

Figure 7

TLR7/8-signaling enhances DCIR-mediated primary CD8+ T-cell response by mDCs. (A) Blood-derived mDCs from an HLA-A201+ donor were targeted with 17nM of anti–DCIR-MART-1 or a control IgG4-MART-1 fusion proteins, activated with CD40L (100 ng/mL), CL075 (1 μg/mL), poly I:C (5 μg/mL), or LPS (50 ng/mL) and cocultured with autologous naive CD8+ T cells for 10 days. The expansion of MART-1–specific CD8+ T cells was measured with a specific HLA-A201-MART-1(26-35) tetramer. Data are of 2 independent experiments with 2 different donors. (B) Blood-derived mDCs from an HLA-A201+ donor were targeted with 30nM of anti–DCIR-MART-1 fusion protein or anti–DCIR-p24, activated with either CD40L or TLR7/8 agonists, and cocultured with autologous naive CD8+ T cells for 10 days. (Top panel) The proportions of HLA-A201-MART-1(26-35) peptide tetramer-positive CD8+ T cells expanded by purified blood mDCs cultured with anti–DCIR-MART-1 fusion protein and activated with either CD40L or TLR7/8 agonist. (Bottom panel) The proportions of HLA-A201-HIV gag p24(151-159) peptide tetramer-positive CD8+ T cells expanded by purified blood mDCs targeted with anti–DCIR-p24 fusion protein and activated with either CD40L or TLR7/8 agonist. Data are of 2 independent experiments with 2 different donors. (C) The expression of intracellular effector molecules Granzyme B and perforin was assessed by flow cytometry on CD8+ T cells primed by IFN-α DCs targeted with 10nM of anti–DCIR-MART-1 or IgG4-MART-1 fusion proteins and activated with CD40L, CL075, or a combination of CD40L and CL075. The expression on the antigen specific MART-1(26-35)-positive cells was analyzed by co staining with the corresponding HLA-A201-tetramer. Data are representative of 2 independent experiments. (D) The frequency of MART-1–specific CD8+ T cells, as measured with a specific HLA-A201-MART-1(26-35) tetramer, after expansion with anti–DCIR-MART-1–targeted DCs that were activated with CD40L, TLR7/8 ligand, or a combination of CD40L and TLR7/8 ligand. IgG4-MART-1 fusion protein or no antigen conditions served as controls. Each dot represents a single experiment. (E top panel) IFN-α DCs were targeted with 17nM of anti–DCIR-MART-1 or a control IgG4-MART-1 fusion proteins, activated with CD40L (100 ng/mL), CL075 (1 μg/mL), poly I:C (10 μg/mL), or LPS (50 ng/mL) and cocultured with autologous naive CD8+ T cells. Ten days later, cells were restimulated with fresh DCs that were loaded with 15mer overlapping peptides derived from the MART-1 protein. Plots show the level of intracytoplasmic IFN-γ by CD8+ T cells after 5-hour stimulation in the presence of monensin. Data are representative of 3 independent experiments. (Bottom panel) Anti–DCIR-p24 or a control IgG4-p24 fusion proteins were used as a model antigen. (F) IFN-α DCs were targeted with 113nM anti–DCIR-MART-1 fusion protein activated with either CD40L (100 ng/mL) or CL075 (1 μg/mL) and cocultured with autologous naive CD8+ T cells. Ten days later, cells were restimulated with fresh DCs that were loaded with 15mer overlapping peptides derived from the MART-1 protein. The levels of IL-4, IL-5, IL-13, IFN-γ, TNF-α, and IL-12p40 were measured by Luminex in the culture supernatant after 24 hours. The graph represents mean ± SD; n = 3. (G) IFN-α DCs were targeted with 10nM anti–DCIR-MART-1 (▴) or a control IgG4-MART-1 (formula image) fusion proteins activated with either CD40L (100 ng/mL) or CL075 (1 μg/mL), or a combination of CD40L and CL075 and cocultured with autologous naive CD8+ T cells. Coculture in the absence of an antigen served as an additional control (□). Ten days later, cells were restimulated with fresh IFN-α DCs that were loaded with MART-1 fusion protein and analyzed by flow cytometry for their intracellular cytokine production. Graphs show the frequency of IFN-γ (left panel) and IFN-γ+TNF-α+ (right panel) producing CD8+ T cells primed by DCIR-targeted, or control IFN-α DCs after 5-hour restimulation in the presence of monensin and 0.25 μg/mL of anti-CD28/CD49d mAb (n = 3).

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