Volume 29, Issue 6, Pages (December 2008)

Slides:



Advertisements
Similar presentations
Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation by Juliette Mouriès, Gabriel Moron, Géraldine Schlecht,
Advertisements

Cheng-Ming Sun, Edith Deriaud, Claude Leclerc, Richard Lo-Man  Immunity 
Volume 28, Issue 2, Pages (February 2008)
The Humoral Immune Response Is Initiated in Lymph Nodes by B Cells that Acquire Soluble Antigen Directly in the Follicles  Kathryn A. Pape, Drew M. Catron,
Identification of CD3+CD4−CD8− T Cells as Potential Regulatory Cells in an Experimental Murine Model of Graft-Versus-Host Skin Disease (GVHD)  Fumi Miyagawa,
Volume 47, Issue 1, Pages e8 (July 2017)
Volume 8, Issue 2, Pages (February 1998)
Wei Hu, Ty Dale Troutman, Ramakrishna Edukulla, Chandrashekhar Pasare 
Hans-Peter Raué, Carol Beadling, Jennifer Haun, Mark K. Slifka 
Volume 31, Issue 2, Pages (August 2009)
by Éric Aubin, Réal Lemieux, and Renée Bazin
Volume 21, Issue 2, Pages (August 2004)
Volume 25, Issue 11, Pages (November 2017)
Volume 11, Issue 12, Pages (June 2015)
Volume 42, Issue 2, Pages (February 2015)
Volume 18, Issue 5, Pages (May 2003)
Ananda W Goldrath, Michael J Bevan  Immunity 
Volume 35, Issue 6, Pages (December 2011)
Dynamic Interplay among Monocyte-Derived, Dermal, and Resident Lymph Node Dendritic Cells during the Generation of Vaccine Immunity to Fungi  Karen Ersland,
Volume 25, Issue 3, Pages (September 2006)
Volume 33, Issue 4, Pages (October 2010)
B-1a and B-1b Cells Exhibit Distinct Developmental Requirements and Have Unique Functional Roles in Innate and Adaptive Immunity to S. pneumoniae  Karen.
Protective Capacity of Memory CD8+ T Cells Is Dictated by Antigen Exposure History and Nature of the Infection  Jeffrey C. Nolz, John T. Harty  Immunity 
Volume 21, Issue 3, Pages (September 2004)
Volume 33, Issue 6, Pages (December 2010)
Volume 13, Issue 12, Pages (December 2015)
Volume 17, Issue 3, Pages (October 2016)
Dynamics of Blood-Borne CD8 Memory T Cell Migration In Vivo
Role of B cells in TH cell responses in a mouse model of asthma
Volume 28, Issue 5, Pages (May 2008)
Volume 18, Issue 5, Pages (May 2003)
Volume 36, Issue 6, Pages (June 2012)
Volume 33, Issue 4, Pages (October 2010)
Volume 13, Issue 6, Pages (November 2015)
Efficient Induction of CD8 T-Associated Immune Protection by Vaccination with mRNA Transfected Dendritic Cells  Shohreh Zarei, Jean-François Arrighi,
Oral Tolerance Can Be Established via Gap Junction Transfer of Fed Antigens from CX3CR1+ Macrophages to CD103+ Dendritic Cells  Elisa Mazzini, Lucia Massimiliano,
Volume 33, Issue 3, Pages (September 2010)
An Interleukin-21- Interleukin-10-STAT3 Pathway Is Critical for Functional Maturation of Memory CD8+ T Cells  Weiguo Cui, Ying Liu, Jason S. Weinstein,
Volume 38, Issue 3, Pages (March 2013)
CD301b+ Dermal Dendritic Cells Drive T Helper 2 Cell-Mediated Immunity
Volume 32, Issue 1, Pages (January 2010)
Opposing Effects of TGF-β and IL-15 Cytokines Control the Number of Short-Lived Effector CD8+ T Cells  Shomyseh Sanjabi, Munir M. Mosaheb, Richard A.
Volume 39, Issue 1, Pages (July 2013)
Volume 29, Issue 5, Pages (November 2008)
CTLA-4 Regulates Induction of Anergy In Vivo
Volume 41, Issue 1, Pages (July 2014)
Volume 29, Issue 4, Pages (October 2008)
T Cells with Low Avidity for a Tissue-Restricted Antigen Routinely Evade Central and Peripheral Tolerance and Cause Autoimmunity  Dietmar Zehn, Michael.
Volume 44, Issue 5, Pages (May 2016)
Volume 31, Issue 4, Pages (October 2009)
Cell-Intrinsic IL-27 and gp130 Cytokine Receptor Signaling Regulates Virus-Specific CD4+ T Cell Responses and Viral Control during Chronic Infection 
Volume 35, Issue 1, Pages (July 2011)
In Vivo Expansion of Regulatory T cells With IL-2/IL-2 mAb Complexes Prevents Anti- factor VIII Immune Responses in Hemophilia A Mice Treated With Factor.
Karima R.R. Siddiqui, Sophie Laffont, Fiona Powrie  Immunity 
Volume 26, Issue 4, Pages (April 2007)
CD44 Regulates Survival and Memory Development in Th1 Cells
Volume 16, Issue 1, Pages (July 2014)
Volume 27, Issue 2, Pages (August 2007)
Susan M. Kaech, Scott Hemby, Ellen Kersh, Rafi Ahmed  Cell 
Volume 32, Issue 1, Pages (January 2010)
Volume 28, Issue 5, Pages (May 2008)
Volume 45, Issue 4, Pages (October 2016)
Volume 38, Issue 6, Pages (June 2013)
Volume 38, Issue 2, Pages (February 2013)
Volume 22, Issue 8, Pages (February 2018)
Volume 31, Issue 2, Pages (August 2009)
Patrizia Stoitzner, Christoph H
Volume 13, Issue 11, Pages (December 2015)
Memory CD8+ T Cells Undergo Peripheral Tolerance
Volume 20, Issue 6, Pages (June 2004)
Presentation transcript:

Volume 29, Issue 6, Pages 934-946 (December 2008) Expression of Costimulatory Ligand CD70 on Steady-State Dendritic Cells Breaks CD8+ T Cell Tolerance and Permits Effective Immunity  Anna M. Keller, Anita Schildknecht, Yanling Xiao, Maries van den Broek, Jannie Borst  Immunity  Volume 29, Issue 6, Pages 934-946 (December 2008) DOI: 10.1016/j.immuni.2008.10.009 Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 1 Characteristics of Transgenic Mice Expressing CD70 under Control of the CD11c Promoter (A) Representative analysis of CD70 cell-surface expression in Cd70tg;Cd27+/− mice. Splenocytes of 6-week-old WT or Cd70tg;Cd27+/− mice were stained with directly conjugated monoclonal antibody (mAb) to CD70 combined with mAb detecting CD11c, CD3, or CD19 and analyzed by flow cytometry. (B) Phenotype of splenic T cells from CD11c-Cd70tg mice on Cd27+/− or Cd27−/− backgrounds and from WT mice of the indicated age. Cells were stained with directly conjugated antibodies to CD3, CD44, and CD62L. Flow-cytometric analysis of cells within the CD3+ gate is shown. Percentages of cells in the CD44loCD62L+ quadrant are indicated. Immunity 2008 29, 934-946DOI: (10.1016/j.immuni.2008.10.009) Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 2 Transgenic CD70 Expression on DC Subsets Splenocytes derived from 6-week-old WT or Cd70tg;Cd27−/− mice were enriched for DCs by density-gradient centrifugation and stained with directly conjugated antibodies to CD11c, B220, and CD70 or CD11c, CD4, CD8α, and CD70 and analyzed by flow cytometry. (A) Gating strategy: pDCs were identified by gating on B220+ CD11clo cells, cDCs by gating on CD11chi and CD4+. CD8+ and CD4−CD8− cDC subsets were identified by gating within the CD11chi population. (B) Cell-surface expression of CD70 on the indicated DC subsets, denoted by mean fluorescence intensity (MFI). (C) WT mice were injected i.v. with LPS alone or in combination with mAb to CD40, and 24 hr later, surface expression of CD70 on CD4+ and CD8+ cDC subsets was compared with that on cDC subsets derived from naive CD11c-Cd70tg;Cd27−/− mice by flow cytometry. Data are representative of two independent experiments. Immunity 2008 29, 934-946DOI: (10.1016/j.immuni.2008.10.009) Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 3 Transgenic CD70 Expression Promotes CD8+ T Cell Expansion and Development of Effector Functions after OVA-Peptide Immunization CD11c-Cd70tg;Cd27−/− or control Cd27−/− recipients received WT or Cd27−/− OT-I T cells. One day after adoptive transfer, mice were challenged i.v. with OVA peptide in PBS. (A) Flow-cytometric analysis of blood cells collected at days 2 and 6 after peptide challenge and stained with OVA257–264-H-2Kb tetramer and mAb to CD8. Numbers within the plots indicate percentages of gated tetramer+ cells within the CD8+ T cell population. (B) Percentages of tetramer+ cells among CD8+ T cells in blood. Data represent mean values (+ SEM) for five mice per group. “∗∗” indicates significant difference between WT OT-I T cell numbers in Cd70tg and control mice for p ≤ 0.01. (C) Flow-cytometric analysis of cell-surface expression of MHC Class II, CD40, and CD80 (MFI) on CD11c+ cells isolated at 24 or 48 hr after immunization with OVA peptide from spleens of groups of mice indicated in (B) (nonimmunized control recipients of WT T cells were not included). The dotted line represents staining with Ig isotype control antibody, and solid lines represent stainings for the indicated markers in different test groups. (D) Intracellular IFNγ staining of CD8+ T cells harvested from spleens at day 6 after OVA-peptide challenge and incubated in vitro for 5 hr in the presence or absence of OVA peptide. Dot plots are representative of three independent experiments. Numbers in quadrants indicate the percentages of IFNγ+ cells within the CD8+ T cell population as means (±SEM) of two mice per group. (E) Cytotoxic activity of OVA-specific T cells in an in vivo cytotoxicity assay. OVA-peptide-pulsed or unpulsed target cells were labeled with high or low CFSE concentration, respectively, and transferred into recipients on day 6 after OVA-peptide challenge. Histograms show the flow-cytometric analysis of CFSE+ cells isolated from spleens 12 hr later. The numbers represent the percentage of specific killing of OVA-pulsed target cells as means (±SEM) of three mice per group. Data are representative of three independent experiments. Immunity 2008 29, 934-946DOI: (10.1016/j.immuni.2008.10.009) Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 4 Transgenic CD70 Expression Generates Immunity to Melanoma Tumors (A–C) CD11c-Cd70tgCd27−/− or control Cd27−/− mice were injected subcutaneously with 1 × 105 B16-OVA tumor cells. Three days later, 105 WT or Cd27−/− OT-I T cells were transferred, and one day later (day 0), mice were challenged with OVA peptide in PBS. (A) Percentages of MHC tetramer+ cells among CD8+ T cells in blood. Data represent mean values (+ SEM) for five mice per group. (B) Absolute numbers of MHC tetramer+ cells among CD8+ T cells in spleens and tumor-draining inguinal lymph nodes (DLN) at day 6 after peptide challenge. Significant differences between WT OT-I T cell numbers in Cd70tg and control mice for ∗∗p ≤ 0.01 in blood and spleen and for ∗p ≤ 0.05 in DLN are indicated. (C) Left: Tumor size measured by caliper. Data represent mean values (+ SEM) for four mice per group. Right: Survival data for the same groups of mice. For symbol legend, see (A). (D–F) CD11c-Cd70tgCd27−/− or control Cd27−/− mice were injected subcutaneously with 1 × 105 B16 tumor cells. One day later, 106 CD8+ Ly5.1+ WT T cells plus 106 pmel-1 T cells were transferred per recipient, and one day later (day 0), mice were challenged with hgp100, TRP-1, and TRP-2 peptides in PBS. (D) Percentages of Ly5.1+ cells among total CD8+ T cells in blood. (E) Tumor size measured by caliper. Data represent mean values (+ SEM) for four mice per group; significant differences for ∗p < 0.05 and ∗∗p < 0.01 are indicated. (F) Survival data for the same groups of mice. For symbol legend, see (D). Immunity 2008 29, 934-946DOI: (10.1016/j.immuni.2008.10.009) Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 5 Acquisition of CD8+ T Cell Memory after Peptide Immunization in Presence of Cd70tg DCs, but Not Cd70tg B Cells CD11c-Cd70tg;Cd27−/−, CD19-Cd70tg;Cd27−/−, or control Cd27−/− recipients received WT or Cd27−/− OT-I T cells. One day after adoptive transfer, mice were challenged i.v. with OVA peptide in PBS. At day 30 after primary challenge, mice were rechallenged i.v. with a combination of LPS, mAb to CD40, and OVA peptide in PBS. (A) Percentages of OVA257–264-H-2Kb tetramer+ cells among CD8+ T cells in blood at the indicated days after primary and secondary OVA challenge. Data represent mean values (+ SEM) for four mice per group. Significant differences between WT OT-I T cell numbers in CD11c-Cd70tg and control mice for ∗∗p ≤ 0.01 and ∗p ≤ 0.05 are indicated. Cell numbers in CD19-Cd70tg mice did not differ significantly from those in control mice. (B) Representative flow-cytometric analysis of blood cells collected at day 6 after rechallenge and stained with OVA257–264-H-2Kb tetramer and CD8 mAb. Numbers within the plots indicate percentages of gated tetramer+ cells within the CD8+ T cell population. (C) Flow-cytometric analysis of CD70 cell-surface expression (MFI) on DCs derived from CD11c-Cd70tg mice and B cells derived from CD19-Cd70tg mice, as determined by combined staining with antibodies to CD11c or CD19 on spleen cells. Immunity 2008 29, 934-946DOI: (10.1016/j.immuni.2008.10.009) Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 6 Antigen Presentation by Resting Cd70tg DCs Induces CD8+ T Cell Priming and Immunity to Viral Infection On day 0, Cd70tg;DIETER and DIETER chimeric mice were control treated or injected with TAM for inducing presentation of transgenic LCMV-derived CD8+ T cell epitopes by DCs. (A) On day 8, blood lymphocytes were stained with MHC tetramers for detecting expansion of GP33–41- or βGal497-505-specific CD8+ T cells (∗p < 0.05, ∗∗p < 0.02). (B) On day 8, mice were challenged with 200 pfu LCMV-WE i.v. On day 4 after infection, acquisition of effector function of GP33–41-specific CD8+ T cells was determined by intracellular IFNγ staining after 5 hr in vitro incubation of splenocytes in the presence of GP33–41 or GP276–286 control peptide (∗p < 0.002). (C) Cd70tg;DIETER chimeric mice treated on day 0 with vehicle, TAM, or TAM plus mAb to CD40 were challenged with 200 pfu LCMV-WE on day 8, and viral titers were determined in the spleen with a focus-forming assay on day 5 after infection. The broken line represents the detection limit of the assay. Data are representative of two independent experiments. Symbols represent individual mice (∗p < 0.02). Immunity 2008 29, 934-946DOI: (10.1016/j.immuni.2008.10.009) Copyright © 2008 Elsevier Inc. Terms and Conditions

Figure 7 Antigen Presentation by Resting Cd70tg DCs Breaks Tolerance For experimental setup, see Figure S5. On day 15, splenocytes were recovered from secondary recipient mice and stimulated in vitro for 5 hr in the presence of brefeldin A with or without 10−5 M GP33–41 peptide. Subsequently, cultures were stained with antibodies directed to CD45.1, CD8, and IFNγ for enumerating the effector TCRtg cells per spleen. Symbols represent individual mice. Incubation with medium instead of peptide induced <1% of TCRtg cells to produce IFNγ (∗p < 0.004). Immunity 2008 29, 934-946DOI: (10.1016/j.immuni.2008.10.009) Copyright © 2008 Elsevier Inc. Terms and Conditions