Candida Species-Dependent Release of IL-12 by Dendritic Cells Induces Different Levels of NK Cell Stimulation

2020 ◽  
Vol 221 (12) ◽  
pp. 2060-2071 ◽  
Author(s):  
Alessandra Marolda ◽  
Kerstin Hünniger ◽  
Sarah Böttcher ◽  
Wolfgang Vivas ◽  
Jürgen Löffler ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Human Blood ◽  
Candida Species ◽  
Cell Activation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Death Receptor ◽  
Bloodstream Infections ◽  
Interleukin 12

Abstract Background Candida albicans and Candida glabrata are the 2 most prevalent Candida species causing bloodstream infections. Patterns of innate immune activation triggered by the 2 fungi differ considerably. Methods To analyze human natural killer (NK) cell activation by both species, we performed ex vivo whole-blood infection assays and confrontation assays with primary human NK cells. Results C. albicans was a stronger activator for isolated human NK cells than C. glabrata. In contrast, activation of blood NK cells, characterized by an upregulated surface exposure of early activation antigen CD69 and death receptor ligand TRAIL, as well as interferon-γ (IFN-γ) secretion, was more pronounced during C. glabrata infection. NK cell activation in blood is mediated by humoral mediators released by other immune cells and does not depend on direct activation by fungal cells. Cross-talk between Candida-confronted monocyte-derived dendritic cells (moDC) and NK cells resulted in the same NK activation phenotype as NK cells in human blood. Blocking experiments and cytokine substitution identified interleukin-12 as a critical mediator in regulation of primary NK cells by moDC. Conclusions Activation of human NK cells in response to Candida in human blood mainly occurs indirectly by mediators released from monocytic cells.

Natural-killer cells and dendritic cells: “l'union fait la force”

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2252-2258 ◽  
Author(s):  
Thierry Walzer ◽  
Marc Dalod ◽  
Scott H. Robbins ◽  
Laurence Zitvogel ◽  
Eric Vivier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Cell Contact ◽  
Ifn Γ

AbstractSeveral recent publications have focused on the newly described interactions between natural-killer (NK) cells and dendritic cells (DCs). Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. Immature DCs appear susceptible to autologous NK-cell-mediated cytolysis while mature DCs are protected. NK-cell-induced DC activation is dependent on both tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) secretion and a cell-cell contact involving NKp30. In vitro, interleukin-12 (IL-12)/IL-18, IL-15, and IFN-α/β production by activated DCs enhance, in turn, NK-cell IFN-γ production, proliferation, and cytotoxic potential, respectively. In vivo, NK-cell/DC interactions may occur in lymphoid organs as well as in nonlymphoid tissues, and their consequences are multiple. By inducing DC activation, NK-cell activation induced by tumor cells can indirectly promote antitumoral T-cell responses. Reciprocally, DCs activated through Toll-like receptors (TLRs) induce potent NK-cell activation in antiviral responses. Thus, DCs and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, emphasizing the role of NK-cell/DC crosstalk in the coordination of innate and adaptive immune responses.

NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3267-3275 ◽  
Author(s):  
Christophe Borg ◽  
Abdelali Jalil ◽  
Diego Laderach ◽  
Kouji Maruyama ◽  
Hiro Wakasugi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Neutralizing Antibodies ◽  
Cell Activation ◽  
Nk Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Loss Of Function ◽  
Knock Out ◽  
Ifn Γ

Abstract Mature dendritic cells (mDCs) can trigger the effector functions of natural killer (NK) cells. Knock-out, small-interfering RNA or neutralizing antibodies targeting interleukin 12 (IL-12) subunits revealed a critical role for IL-12 in NK cell interferon γ (IFN-γ) secretion promoted by mDCs. However, NK cell activation by DCs also required direct cell-to-cell contacts. DC-mediated NK cell activation involved the formation of stimulatory synapses between DCs and NK cells. The formation of DC/NK cell conjugates depended on cytoskeleton remodeling and lipid raft mobilization in DCs. Moreover, the disruption of the DC cytoskeleton using pharmacologic agents or the loss-of-function mutation of the Wiskott-Aldrich syndrome protein abolished the DC-mediated NK cell activation. Synapse formation promoted the polarized secretion of preassembled stores of IL-12 by DCs toward the NK cell. The synaptic delivery of IL-12 by DCs was required for IFN-γ secretion by NK cells, as assessed using inhibitors of cytoskeleton rearrangements and transwell experiments. Therefore, the cross-talk between DCs and NK cells is dictated by functional synapses. (Blood. 2004;104:3267-3275)

scholarly journals Dengue Virus-Infected Dendritic Cells, but Not Monocytes, Activate Natural Killer Cells through a Contact-Dependent Mechanism Involving Adhesion Molecules

mBio ◽  
2017 ◽  
Vol 8 (4) ◽  
Author(s):  
Vivian Vasconcelos Costa ◽  
Weijian Ye ◽  
Qingfeng Chen ◽  
Mauro Martins Teixeira ◽  
Peter Preiser ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Virus Infection ◽  
Dengue Virus ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cell Activation ◽  
Nk Cell ◽  
Denv Infection ◽  
Ifn Γ

ABSTRACT Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using an optimized humanized mouse model, we show that human NK cells, through the secretion of gamma interferon (IFN-γ), are critical in the early defense against DENV infection. Depletion of NK cells or neutralization of IFN-γ leads to increased viremia and more severe thrombocytopenia and liver damage in humanized mice. In vitro studies using autologous human NK cells show that DENV-infected monocyte-derived dendritic cells (MDDCs), but not monocytes, activate NK cells in a contact-dependent manner, resulting in upregulation of CD69 and CD25 and secretion of IFN-γ. Blocking adhesion molecules (LFA-1, DNAM-1, CD2, and 2β4) on NK cells abolishes NK cell activation, IFN-γ secretion, and the control of DENV replication. NK cells activated by infected MDDCs also inhibit DENV infection in monocytes. These findings show the essential role of human NK cells in protection against acute DENV infection in vivo, identify adhesion molecules and dendritic cells required for NK cell activation, and delineate the sequence of events for NK cell activation and protection against DENV infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection.

Fibronectin maintains survival of mouse natural killer (NK) cells via CD11b/Src/β-catenin pathway

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4081-4088 ◽  
Author(s):  
Ting Zhang ◽  
Shuxun Liu ◽  
Pengyuan Yang ◽  
Chaofeng Han ◽  
Jianli Wang ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nuclear Translocation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Interleukin 12 ◽  
Erk Phosphorylation ◽  
Extracellular Signal ◽  
B Cell Leukemia

Abstract Tissue microenvironment and stroma-derived extracellular matrix (ECM) molecules play important roles in the survival and differentiation of cells. Mouse natural killer (NK) cells usually die within 24 hours once isolated ex vivo. Exogenous cytokines such as interleukin-12 (IL-12) and IL-15 are required to maintain the survival and activity of mouse NK cells cultured in vitro. Whether and how ECM molecules such as fibronectin can support the survival of NK cells remain unknown. We demonstrate that fibronectin, just like IL-15, can maintain survival of mouse NK cells in vitro. Furthermore, we show that fibronectin binds to the CD11b on NK cells, and then CD11b recruits and activates Src. Src can directly interact with β-catenin and trigger nuclear translocation of β-catenin. The activation of β-catenin promotes extracellular signal-related kinase (ERK) phosphorylation, resulting in the increased expression of antiapoptotic protein B-cell leukemia 2 (Bcl-2), which may contribute to the maintenance of NK-cell survival. Consistently, fibronectin cannot maintain the survival of CD11b− NK cells and β-catenin–deficient NK cells in vitro, and the number of NK cells is dramatically decreased in the β-catenin–deficient mice. Therefore, fibronectin can maintain survival of mouse NK cells by activating ERK and up-regulating Bcl-2 expression via CD11b/Src/β-catenin pathway.

Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3253-3262 ◽  
Author(s):  
Thanyalak Tha-In ◽  
Herold J. Metselaar ◽  
Hugo W. Tilanus ◽  
Zwier M. A. Groothuismink ◽  
Ernst J. Kuipers ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Intravenous Immunoglobulins ◽  
Interferon Γ ◽  
T Cell Priming ◽  
Induced Apoptosis

AbstractThe modes of action of intravenous immunoglobulins (IVIgs) in exerting their immunomodulatory properties are broad and not fully understood. IVIgs can modulate the function of various immune cells, including suppressing the capacity of dendritic cells (DCs) to stimulate T cells. In the present study, we showed that DCs matured in the presence of IVIgs (IVIg-DCs) activated NK cells, and increased their interferon-γ production and degranulation. The activated NK cells induced apoptosis of the majority of IVIg-DCs. In consequence, only in the presence of NK cells, IVIg-DCs were 4-fold impaired in their T-cell priming capacity. This was due to NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) to IVIg-DCs, probably induced by IgG multimers, which could be abrogated by blockade of CD16 on NK cells. Furthermore, IVIg-DCs down-regulated the expression of NKp30 and KIR receptors, and induced the generation of CD56brightCD16−CCR7+ lymph node–type NK cells. Our results identify a novel pathway, in which IVIgs induce ADCC of mature DCs by NK cells, which downsizes the antigen-presenting pool and inhibits T-cell priming. By influencing the interaction between DCs and NK cells, IVIgs modulate the ability of the innate immunity to trigger T-cell activation, a mechanism that can “cool down” the immune system at times of activation.

Enhanced NK Cell Activation, Cytotoxicity and Ex-Vivo Expansion (EvE) of Cryopreserved Cord Blood (CB) Natural Killer (NK) Cells: Potential Role for CB NK Cells in Adoptive Cellular Immunotherapy (ACI).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 726-726
Author(s):  
Janet Ayello ◽  
Julia Nemiroff ◽  
Prakash Satwani ◽  
Carmella van de Ven ◽  
Evan Shereck ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Granzyme B ◽  
Cellular Immunotherapy ◽  
Common Mechanism ◽  
Short Term ◽  
Cd107a Expression ◽  
Short Term Culture

Abstract CD56+ NK subsets exhibit differential NK receptors (NKR ) such as NCR profiles including killer-Ig-like receptors (KIR), C-lectin (NKG2) and natural cytoxicity receptors (NCR) involved with tumor target recognition (Farag et al Blood, 2002). NK cell activation and NK mediated cytolysis is induced by several NKRs such as NCR (i.e. NKp44, NKp46) and NKG2 surface receptors like NKG2D (Moretta et al, Curr Opinion in Immunol, 2004). Target cell killing by activated NK cells via the granule-dependent pathway is a common mechanism of NK and CTLs and degranulation is followed by the expression of lysosomal-associated membrane protein-1 [LAMP-1] on the cell surface (Penack et al, Leukemia, 2005). CB is limited by the absence of available donor effector cells (NK, CTL, LAK and NKT cells) for infusion after UCBT (Cairo, et al, Transfusion, 2005). We have demonstrated the ability to EvE CB in short-term culture (48 hrs) with IL-2, IL-7, IL-12 and anti-CD3 (ABCY) cryopreserved, thawed, recryopreserved, rethawed and EvE (CTCTE) CB with significant increase in CD3−/16+/56+ bright/dim subsets expressing KIR3DL1, KIR2DL1/S1, KIR2DL2 and CD94/NKG2a (Ayello/Cairo et al BBMT, 2006). In this study, we compared short-term culture (48 hrs) with prolonged cultures (4 to 10 days) on expansion, expression of NCR, NKG2, KIR and cytolytic ability and mechanisms in CTCTE CB. Rethawed nonadherent CB cells were cultured (2–10 days) in serum-free media alone or with anti-CD3 (50 ng/ml), IL-2 (5 ng/ml), IL-7 (10 ng/ml) and IL-12 (10 ng/ml) [ABCY]. NKR expression (CD94, NKG2D, Nkp44 and KIR2DS4), intracellular perforin, granzyme B activity and LAMP-1 receptor (CD107a) expression were determined by flow cytometry. Cytoxicity was measured by europium release assay and tumor targets used were K562, Daudi, neuroblastoma (SHSY5Y) and AML (Kasumi-1) at a 20:1 E:T ratio. C-lectin activating receptor CD94/NKG2D was increased at day 7 vs 2 following ABCY EvE (41.4±0.43 vs 23.7±2.%, p<0.001). Significant increases were seen in activating KIR2DS4 at day 10 vs 2 in ABCY in both CD3−/16+/56+dim and bright subsets (16.9±0.4 vs 2.1±0.2% and 22.3±0.3 vs 0.9± 0.2%, p<0.001, respectively). In contrast, NCR expression in CD3−/16+/56+dim NKp44 subset was significantly decreased at day 10 vs 2 of EvE CB in ABCY (15.2±0.7 vs 27.2±0.7%, p<0.001). Granzyme B expression was increased from day 2 to 10 (25.8± vs 45.1± 1.7%, p<0.001) yet perforin was decreased in EvE CB in ABCY at day 7 vs 2 (68.3±2.19 vs 84.3±1.3%, p<0.001). CD107a expression was significantly increased at day 7 vs 2 in ABCY EvE CB (12.95±1.47 vs 69.34±2.22%, p<0.001). In addition, significant increases in cytolytic activity was demonstrated at day 7 vs 2 of EvE CB cells in ABCY against tumor targets K562 (71.5±±0.81 vs 53.8±3.9%, p<0.001), Daudi (63.9±0.73 vs 31.8±1.8%, p<0.001), SYSY5Y (76.8±6.5 vs 57.5±3.4%, p<0.05) and Kasumi-1 (56.6.5±0.4 vs 38±1.1%, p<0.001). In summary, CB MNC may be thawed at time of CB transplantation, recryopreserved, rethawed at a later date, EvE and activated for up to 10 days to yield significantly increased cytotolytic activity against NHL, AML and neuroblastoma with increased expression of NK KAR KIR2DS4 and granzyme B, LAMP-1 degranulation (NK activation) but decreased NK C-lection CD94/NKG2D, NCR NKp44 and perforin expression.

Immunostimulatory Properties of the Human Ortholog of the GMCSF/IL2 Fusion Protein for Cell Based Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4894-4894
Author(s):  
Claudia Penafuerte Graduate ◽  
Jacques Galipeau
Keyword(s):  
Fusion Protein ◽  
Nk Cells ◽  
Cell Expansion ◽  
Cell Activation ◽  
Nk Cell ◽  
Ex Vivo ◽  
Potential Candidate ◽  
Activation Markers ◽  
Cell Based Therapy

Abstract NK cells constitute a potential candidate for cancer cell therapy because they express a diverse array of inhibitory and activating receptors, which recognize and kill infected or tumor cells without prior immune sensitization. However, autologous NK cell mediated adoptive immunotherapy is restricted due to insufficient cytolytic activity of NK cells from patient with aggressive malignancies. In contrast, the infusion of alloreactive NK cells has shown more successful outcomes in the treatment of cancer, but this approach also presents difficulties such as the high doses of cytokines required to induce NK cell expansion ex vivo, which may also sensitize NK cells to apoptosis. Therefore, a critical issue for NK cell based therapy is the use of appropriate growth factors or cytokines that promote NK cell expansion and activation. We have previously shown that a murine GM-CSF/IL-2 fusion protein (aka GIFT2) displays novel antitumor properties in vivo compared to both cytokines in combination regarding tumor site recruitment of macrophages and significant functional NK cell infiltration [Stagg et al., Cancer Research (December 2004)]. In the present work, we found that human GIFT2 will lead to a substantial two fold proliferation of human blood-derived NK cells which is significantly (p<0.05) superior to either IL2 or GMCSF single cytokine treatment or both cytokines combined at equimolar concentration. In addition, we observed that GIFT2 leads to robust expression of NK-cell activation markers CD69 and CD107a. In conclusion, the human GIFT2 fusokine is a novel and potent tool for ex vivo expansion of activated NK cells which may be of use in cell-based immunotherapy of cancer.

scholarly journals Activation of Human NK Cells by Staphylococci and Lactobacilli Requires Cell Contact-Dependent Costimulation by Autologous Monocytes

2002 ◽  
Vol 9 (3) ◽  
pp. 649-657 ◽  
Author(s):  
D. Haller ◽  
P. Serrant ◽  
D. Granato ◽  
E. J. Schiffrin ◽  
S. Blum
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Interleukin 12 ◽  
Accessory Cell ◽  
Cell Contact ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Ifn Γ

ABSTRACT NK cells are instrumental in innate immune responses, in particular for the early production of gamma interferon (IFN-γ) and other cytokines necessary to control certain bacterial, parasitic, and viral infections. NK cell-mediated effector functions are controlled by a fine balance between distinct receptors mediating activating and inhibitory signals; however, little is known about activating receptors on NK cells and their corresponding ligands. Several studies have shown that commensal lactobacilli isolated from the human gastrointestinal tract activate human mononuclear cells and are potent inducers of IFN-γ and monocyte-derived interleukin 12 (IL-12). NK cell activation was shown for Lactobacillus johnsonii La1. In this study the cellular mechanisms of in vitro NK cell activation by gram-positive bacteria were analyzed. Staphylococcus aureus- and L. johnsonii La1-mediated activation of CD3− CD16+ CD56+ human peripheral blood NK cells, including expression of the activation antigen CD69 and secretion of IFN-γ, required cell contact-dependent costimulation by autologous monocytes. S. aureus- and L. johnsonii-preactivated monocytes retained their capacity to induce NK cell activation. In contrast, cytokine-primed monocytes completely failed to induce NK cell activation unless bacteria were present. This suggests that phagocytosis of bacteria provided additional coactivation signals on accessory cells that may differ from those induced by tumor necrosis factor and IFN-γ. Blocking of costimulatory molecules by B7.1, B7.2, and IL-12 but not CD14 monoclonal antibodies inhibited S. aureus- and L. johnsonii-induced effector function of NK cells. Our data suggest an important role for accessory cell-derived signals in the process of NK cell activation by gram-positive bacteria.

scholarly journals Distinct and complementary functions of MDA5 and TLR3 in poly(I:C)-mediated activation of mouse NK cells

2009 ◽  
Vol 206 (13) ◽  
pp. 2967-2976 ◽  
Author(s):  
Stephen McCartney ◽  
William Vermi ◽  
Susan Gilfillan ◽  
Marina Cella ◽  
Theresa L. Murphy ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Poly I:C ◽  
Interleukin 12 ◽  
Interferon Α ◽  
Accessory Cells ◽  
A Minor ◽  
Bone Marrow Chimeras

The double-stranded RNA (dsRNA) analogue poly(I:C) is a promising adjuvant for cancer vaccines because it activates both dendritic cells (DCs) and natural killer (NK) cells, concurrently promoting adaptive and innate anticancer responses. Poly(I:C) acts through two dsRNA sensors, Toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein-5 (MDA5). Here, we investigated the relative contributions of MDA5 and TLR3 to poly(I:C)-mediated NK cell activation using MDA5−/−, TLR3−/−, and MDA5−/−TLR3−/− mice. MDA5 was crucial for NK cell activation, whereas TLR3 had a minor impact most evident in the absence of MDA5. MDA5 and TLR3 activated NK cells indirectly through accessory cells and induced the distinct stimulatory cytokines interferon-α and interleukin-12, respectively. To identify the relevant accessory cells in vivo, we generated bone marrow chimeras between either wild-type (WT) and MDA5−/− or WT and TLR3−/− mice. Interestingly, multiple accessory cells were implicated, with MDA5 acting primarily in stromal cells and TLR3 predominantly in hematopoietic cells. Furthermore, poly(I:C)-mediated NK cell activation was not notably impaired in mice lacking CD8α DCs, providing further evidence that poly(I:C) acts through diverse accessory cells rather than solely through DCs. These results demonstrate distinct yet complementary roles for MDA5 and TLR3 in poly(I:C)-mediated NK cell activation.

scholarly journals Vaccination with Live Leishmania major and CpG DNA Promotes Interleukin-2 Production by Dermal Dendritic Cells and NK Cell Activation

2009 ◽  
Vol 16 (11) ◽  
pp. 1601-1606 ◽  
Author(s):  
Eva Maria Laabs ◽  
Wenhui Wu ◽  
Susana Mendez
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Cell Activation ◽  
Leishmania Major ◽  
Nk Cell ◽  
Natural Infection ◽  
Interleukin 2 ◽  
Innate Immune Responses ◽  
Cpg Dna ◽  
Ifn Γ

ABSTRACT Cutaneous leishmaniasis due to Leishmania major is an emerging, chronic parasitic disease that causes disfigurement and social stigmatization. Drug therapy is inadequate, and there is no vaccine. Inoculation of virulent parasites (leishmanization) is the only intervention that has ever provided protection, because it mimics natural infection and immunity, but it was discontinued due to safety concerns (uncontrolled vaccinal lesions). In an effort to retain the benefits (immunity) while avoiding the side effects (lesions) of leishmanization, we immunized C57BL/6 mice with L. major and CpG DNA (Lm/CpG). This combination prevented lesions while inducing immunity. Also, the vaccination with live parasites and the Toll-like receptor 9 agonist enhanced innate immune responses by activating dermal dendritic cells (DCs) to produce cytokines. Here we report that the Lm/CpG vaccine induced dermal DCs, but not bone marrow-derived DCs, to produce interleukin-2 (IL-2). The release of this unusual DC-derived cytokine was concomitant with a peak in numbers of NK cells that produced gamma interferon (IFN-γ) and also enhanced activation of proliferation of IFN-γ+ CD4+ T cells. Parasite growth was controlled in Lm/CpG-vaccinated animals. This is the first demonstration of the ability of dermal DCs to produce IL-2 and of the activation of NK cells by vaccination in the context of leishmaniasis. Understanding how the Lm/CpG vaccine enhances innate immunity may provide new tools to develop vaccines against L. major, other chronic infectious diseases, or other conditions, such as cancer.

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