Interferon-producing Killer Dendritic Cells Research Articles

Characterization of tumoricidal activities mediated by a novel immune cell regimen composing interferon-producing killer dendritic cells and tumor-specific cytotoxic T lymphocytes

BackgroundAlthough immune cell therapy has long been used for treating solid cancer, its efficacy remains limited. Interferon (IFN)-producing killer dendritic cells (IKDCs) exhibit cytotoxicity and present antigens to relevant cells; thus, they can selectively induce tumor-associated antigen (TAA)-specific CD8 T cells and may be useful in cancer treatment. Various protocols have been used to amplify human IKDCs from peripheral sources, but the complexity of the process has prevented their widespread clinical application. Additionally, the induction of TAA-specific CD8 T cells through the adoptive transfer of IKDCs to immunocompromised patients with cancer may be insufficient. Therefore, we developed a method for generating an immune cell-based regimen, Phyduxon-T, comprising a human IKDC counterpart (Phyduxon) and expanded TAA-specific CD8 T cells.MethodsPeripheral blood mononuclear cells from ovarian cancer patients were cultured with human interleukin (hIL)-15, hIL-12, and hIL-18 to generate Phyduxon-T. Then, its phenotype, cytotoxicity, and antigen-presenting function were evaluated through flow cytometry using specific monoclonal antibodies.ResultsPhyduxon exhibited the characteristics of both natural killer and dendritic cells. This regimen also exhibited cytotoxicity against primary ovarian cancer cells and presented TAAs, thereby inducing TAA-specific CD8 T cells, as evidenced by the expression of 4-1BB and IFN-γ. Notably, the Phyduxon-T manufacturing protocol effectively expanded IFN-γ-producing 4-1BB+ TAA-specific CD8 T cells from peripheral sources; these cells exhibited cytotoxic activities against ovarian cancer cells.ConclusionsPhyduxon-T, which is a combination of natural killer cells, dendritic cells, and TAA-specific CD8 T cells, may enhance the efficacy of cancer immunotherapy.

T-bet transduction enhances anti-tumor efficacy of IFN-producing dendritic cell (IKDC) against hepatocellular carcinoma via apoptosis induction

Hepatocellular carcinoma (HCC) remains a public health challenge that requires dedication to develop new treatment options due to its high recurrence rate and poor prognosis. Interferon-producing killer dendritic cell (IKDC) is a subset of INF-γ secreting immune cells that modulates acquired immunity and possesses cytolytic ability. We modified IKDC isolated from the murine spleen with T-bet lentiviral transduction to enhance its cytotoxicity against HCC, and acquired IKDC overexpressing T-bet (T-bet-IKDC) for the first time. T-bet-IKDC has increased INF-γ secretion and surface expression of NKG2D and TRAIL. In vitro study by MTS assay and flow cytometry showed enhanced anti-tumor effect against H22 cells via apoptosis induction in a dose- and time-dependent manner. In vivo study on H22-bearing mice confirmed increased INF-γ secretion, reduced tumor size, increased caspase 3 cleavage, and up-regulation of cytotoxic molecules after T-bet-IKDC administration. The study suggested prospective application of T-bet-IKDC in future immunotherapy for HCC treatment.

Effect of Multiple Vaccinations with Tumor Cell-Based Vaccine with Codon-Modified GM-CSF on Tumor Growth in a Mouse Model.

Ectopic expression of codon-modified granulocyte-macrophage colony-stimulating factor (cGM-CSF) in TC-1 cells (TC-1/cGM-CSF), a model cell line for human papillomavirus (HPV)-infected cervical cancer cells, increased the expression level of GM-CSF and improved the efficacy of tumor cell-based vaccines in a cervical cancer mouse model. The number of vaccine doses required to induce a long-term immune response in a cervical cancer mouse model is poorly understood. Here, we investigated one, three, and five doses of the irradiated TC-1/cGM-CSF vaccine to determine which dose was effective in inducing a greater immune response and the suppression of tumors. Our findings showed that three doses of irradiated TC-1/cGM-CSF vaccine elicited slower tumor growth rates and enhanced survival rates compared with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Consistently, mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine exhibited stronger interferon gamma (IFN-γ) production in HPV E7-specific CD8+ T cells and CD4+ T cells. A higher percentage of natural killer cells and interferon-producing killer dendritic cells (IKDCs) appeared in the splenocytes of the mice vaccinated with three doses of irradiated TC-1/cGM-CSF vaccine compared with those of the mice vaccinated with one dose or five doses of irradiated TC-1/cGM-CSF vaccine. Our findings demonstrate that single or multiple vaccinations, such as five doses, with irradiated TC-1/cGM-CSF vaccine suppressed the immune response, whereas three doses of irradiated TC-1/cGM-CSF vaccine elicited a greater immune response and subsequent tumor suppression.

IL-15 Generates IFN-γ-producing Cells Reciprocally Expressing Lymphoid-Myeloid Markers during Dendritic Cell Differentiation.

Recently, interest in IL-15-differentiated cells has increased; however, the phenotypic definition of IL-15-differentiated bone marrow-derived cells (IL-15-DBMCs) is still under debate, particularly the generation of IFN-γ-producing innate cells such as premature NK (pre-mNK) cells, natural killer dendritic cells (NKDCs), interferon-producing killer dendritic cells (IKDCs), and type 1 innate lymphoid cells (ILC1s), all of which are IL-15-dependent. Here, we revisited the immunophenotypic characteristics of IFN-γ-producing IL-15-DBMCs and their functional role in the control of intracellular Mycobacterium tuberculosis (Mtb) infection. When comparing the cytokine levels between bone marrow-derived dendritic cells (BMDCs) and IL-15-DBMCs upon stimulation with various TLR agonists, only the CD11cint population of IL-15-DBMCs produced significant levels of IFN-γ, decreased levels of MHC-II, and increased levels of B220. Neither BMDCs nor IL-15-DBMCs were found to express DX5 or NK1.1, which are representative markers for the NK cell lineage and IKDCs. When the CD11cintB220+ population of IL-15-DBMCs was enriched, the Thy1.2+Sca-1+ population showed a marked increase in IFN-γ production. In addition, while depletion of the B220+ and Thy1.2+ populations of IL-15-DBMCs, but not the CD19+ population, inhibited IFN-γ production, enrichment of these cell populations increased IFN-γ. Ultimately, co-culture of sorted IFN-γ-producing B220+Thy1.2+ IL-15-DBMCs with Mtb-infected macrophages resulted in control of the intracellular growth of Mtb via the IFN-γ-nitric oxide axis in a donor cell number-dependent manner. Taken together, the results indicate that IFN-γ-producing IL-15-DBMCs could be redefined as CD11cintB220+Thy1.2+Sca-1+ cells, which phenotypically resemble both IKDCs and ILC1s, and may have therapeutic potential for controlling infectious intracellular bacteria such as Mtb.

A role for pre-mNK cells in tumor progression.

The innate and adaptive immune systems have evolved together to fight infection and cancerous tissues. The innate immune system emerges first with the adaptive immune system following, both ostensibly being bridged by dendritic cells (DC). Recently cells have emerged that possess characteristics of both innate and adaptive immune cell qualities, termed interferon-producing killer dendritic cells (IKDCs). These cells have an indistinct origin that is not well understood. They appear to have more NK cell attributes than DC but purportedly can regulate the immune system similar to immunoregulatory NK cells. Because of this, they have been renamed pre-mNK cells (pre-mature NK cells). We argue in this commentary that pre-mNK cells may contribute to cancer recurrence.

Depletion of B220+NK1.1+ cells enhances the rejection of established melanoma by tumor-specific CD4+ T cells

Five-year survival rates for patients diagnosed with metastatic melanoma are less than 5%. Adoptive cell transfer (ACT) has achieved an objective response of 50% by Response Evaluation Criteria in Solid Tumors (RECIST) in this patient population. For ACT to be maximally effective, the host must first be lymphodepleted. It is hypothesized that lymphodepletion may remove regulatory elements and cytokine sinks, or increase the activation and availability of antigen presenting cells (APCs). We use an in vivo model to study the ACT of tumor-associated antigen (TAA)-specific CD4+ T cells (TRP-1 cells). We have discovered that depletion of NK1.1+ cells enhances the rejection of established melanoma tumors by adoptively transferred TRP-1 CD4+ T cells. NK1.1+ cell depletion increases the number of CD4+ T cells, the serum concentration of pro-inflammatory cytokines, autoimmune vitiligo, host survival and prevented recurrence after ACT. Because multiple cells express NK1.1, we targeted different NK1.1+ cell populations using antibodies specific for NK cells, pre-mNK cells, and innate lymphoid cells (ILCs). Our data suggests that NK1.1+B220+ pre-mNK cells (also known as interferon-producing killer dendritic cells; IKDCs) are an important inhibitor of the CD4+ T cell response to melanoma. Understanding this mechanism may help design new immunotherapies to modulate the activity of pre-mNKs in the face of an antitumor immune response and inhibit their suppression of adoptively transferred T cells.

Lactotransferrin-Cre reporter mice trace neutrophils, monocytes/macrophages and distinct subtypes of dendritic cells

Considerable effort has been expended to identify genes that account for myeloid lineage commitment and development. However, currently available non-invasive mouse models utilize myeloid-specific reporters that are significantly expressed in hematopoietic stem cells as well as lymphoid compartments. Here, we describe a myeloid-specific marker that is not shared by any other lineage. We show that lactotransferrin mRNA is expressed by Gr-1(+)/CD11b(+) cells in the bone marrow, as opposed to hematopoietic stem cells or any peripheral cell population. To follow the progeny of lactotransferrin-expressing bone marrow cells, we generated a mouse model in which a reporter gene is irreversibly activated from the lactotransferrin-promoter. We found that lactotransferrin-reporter labels a majority of neutrophils, monocytes, macrophages and distinct subtypes of dendritic cells, while excluding T, B, natural killer cells, interferon-producing killer dendritic cells, plasmacytoid dendritic cells, erythrocytes and eosinophils. Lactotransferrin-reporter(-) bone marrow cells retain lymphoid, erythroid and long-term repopulating potential, while lactotransferrin-reporter(+) bone marrow cells confer only myeloid, but not lymphoid potential. We conclude that lactotransferrin represents a late stage differentiation marker of neutrophils, macrophages and distinct subtypes of dendritic cells.

Revisiting the Prominent Anti-Tumoral Potential of Pre-mNK Cells

Interferon-producing killer dendritic cells (IKDC) were first described for their outstanding anti-tumoral properties. The “IKDC” terminology implied the description of a novel DC subset and initiated a debate on their cellular lineage origin. This debate shifted the focus away from their notable anti-tumoral potential. IKDC were recently redefined as precursors to mature NK (mNK) cells and consequently renamed pre-mNK cells. Importantly, a putative human equivalent of pre-mNK cells was recently associated with improved disease outcome in cancer patients. It is thus timely to revisit the functional attributes as well as the therapeutic potential of pre-mNK cells in line with their newly defined NK-cell precursor function.

Redefining interferon-producing killer dendritic cells as a novel intermediate in NK-cell differentiation

AbstractThe cell lineage origin of IFN-producing killer dendritic cells (IKDCs), which exhibit prominent antitumoral activity, has been subject to debate. Although IKDCs were first described as a cell type exhibiting both plasmacytoid DC and natural killer (NK) cell properties, the current view reflects that IKDCs merely represent activated NK cells expressing B220, which were thus renamed B220+ NK cells. Herein, we further investigate the lineage relation of B220+ NK cells with regard to other NK-cell subsets. We surprisingly find that, after adoptive transfer, B220− NK cells did not acquire B220 expression, even in the presence of potent activating stimuli. These findings strongly argue against the concept that B220+ NK cells are activated NK cells. Moreover, we unequivocally show that B220+ NK cells are highly proliferative and differentiate into mature NK cells after in vivo adoptive transfer. Additional phenotypic, functional, and transcriptional characterizations further define B220+ NK cells as immediate precursors to mature NK cells. The characterization of these novel attributes to B220+ NK cells will guide the identification of their ortholog in humans, contributing to the design of potent cancer immunotherapies.

Tolerogen-induced interferon-producing killer dendritic cells (IKDCs) protect against EAE

Natural killer (NK) cells and dendritic cells (DCs) have been shown to link the innate and adaptive immune systems. Likewise, a new innate cell subset, interferon-producing killer DCs (IKDCs), shares phenotypic and functional characteristics with both DCs and NK cells. Here, we show IKDCs play an essential role in the resolution of experimental autoimmune encephalomyelitis (EAE) upon treatment with the tolerizing agent, myelin oligodendrocyte glycoprotein (MOG), genetically fused to reovirus protein σ1 (termed MOG-pσ1). Activated IKDCs were recruited subsequent MOG-pσ1 treatment of EAE, and disease resolution was abated upon NK1.1 cell depletion. These IKDCs were able to kill activated CD4 + T cells and mature dendritic DCs, thus, contributing to EAE remission. In addition, IKDCs were responsible for MOG-pσ1-mediated MOG-specific regulatory T cell recruitment to the CNS. The IKDCs induced by MOG-pσ1 expressed elevated levels of HVEM for interactions with cognate ligand-positive cells: LIGHT + NK and T eff cells and BTLA + B cells. Further characterization revealed these activated IKDCs being MHC class II high, and upon their adoptive transfer (CD11c +NK1.1 +MHC class II high), IKDCs, but not CD11c +NK1.1 +MHC class II intermediate/low (unactivated) cells, conferred protection against EAE. These activated IKDCs showed enhanced CD107a, PD-L1, and granzyme B expression and could present OVA, unlike unactivated IKDCs. Thus, these results demonstrate the interventional potency induced HVEM + IKDCs to resolve autoimmune disease.

Role of interferon-producing killer dendritic cells in the development of autoimmune disease (44.14)

Abstract Interferon-producing killer dendritic cells (IKDCs) share functional characteristics with NK cells and DCs. We investigated their role in the autoimmune disease developed by transgenic mice that overexpress TLR7 (TLR7tg). We determined that a cell population resembling IKDCs expands in TLR7tg mice through their intrinsic sensitivity to TLR7 stimulation. We confirmed that they are bona fide NK cells by their ability to kill cells lacking MHC I molecules in vitro. These cells were also able to present antigen to naïve T cells in in vitro assays. Adoptive transfer of IKDCs isolated from TLR7tg mice into wild type mice induced priming and activation of naïve T cells. In vitro stimulation with TLR7 agonists of IKDCs derived from TLR7tg resulted in the production of TNFa, MCP-1, IFNa and high levels of IL-10. We also tested the requirement of cytokines that are essential for NK cell development. We found that the expansion of IKDCs in TLR7tg mice was IL15 dependent but IL18 independent. We observed that lack of IL15 reduced many pro-inflammatory subsets (Ly6C+monocytes, granulocytes, DCs and memory T cells) and delayed the development of glomerulonephritis in TLR7tg mice. These results reveal expansion of IKDCs in autoimmune inflammatory conditions and suggest a dual role for these cells in both the priming of autoreactive T cells and the release of inflammatory cytokines.

Immunology and Gene Therapy: Shoulder to Shoulder Into the Fray: International Symposium: Critical Frontiers Between Immunity and Gene Therapy Pamplona, Spain, 27–28 October 2009

Functions of the immune system are critical for the outcome of gene therapy. Immunologists, virologists, and gene therapists met in Pamplona, Spain, in October 2009 to present and analyze common frontiers in these fields under the auspices of the Ramon Areces Foundation (http://www.fundacionareces.es). Antibodies and cell-mediated immune mechanisms can be either friends or foes in gene therapy. A form of Murphy’s law seems to apply: “If an immune response is to be induced, it will usually be weak. If an immune response is to be avoided, it will be almost always neutralizing.”

Interferon producing killer dendritic cells (IKDC): A matter of controversy

Division of labour among cells of the immune system is a prevailing theme in the orchestration of immune responses. Contrary to this paradigm, a particular leukocyte population in the mouse seems to be equipped with the ability to kill transformed and virally infected cells and with the capability to mediate antigen processing and presentation to T cells. Those two functions are classically ascribed separately to Natural Killer (NK) cells and Dendritic cells (DC). IKDC (interferon-producing killer dendritic cell) were defined in mice as cells expressing CD11c, although to a lesser extent than conventional DCs (cDCs), while coexpressing B220, NK1.1, CD49b (VLA-2) and MHC Class II molecules. Absence of CD3, CD19 and Gr1(Ly49c) expression also featured this minor subset upon multicolour FACS characterization. These cells kill a variety tumor cell lines in a TRAIL-dependent fashion. Furthermore, IKDC produce high amounts of Interferon (IFN) gamma (IFN-γ) and type I IFN upon activation by combined interleukins (IL-18, IL-2, IL-12 or IL-15), tumor cells, or TLR-9 nucleotide agonists. Importantly, these cells may present antigen to prime CD4 and CD8 T cells. The discovery of this subset in mice was reported in two back to back articles published in Nature Medicine in 2006, along with a comment that highlighted how such a cell may provide the ability to kill cells in an innate fashion while starting T-cell adaptive immunity by means of cross-presentation of antigens collected from the apoptotic remains of their victim cells. However, two years later three articles in a single issue of the Journal of Experimental Medicine contended that such a population did not exist and that IKDC were actually nothing more than activated NK cells. The arguments were based on the inability of IKDC to present antigen and prime T cells, and on their dependency on IL-15 for differentiation and survival. Later on, the groups that first described IKDC have provided evidence that such a subpopulation can mediate antigen presentation and have also stressed several characteristics that discriminate activated NK cells and IKDC. The reasons for some of these experimental discrepancies are obscure. Yet, the core of the controversy is to establish wether the hybrid abilities proposed for such minor leukocyte population are relevant to physiology, pathology or therapy. To date, no equivalent population has been described in human lymphoid tissues.

Both Conventional and Interferon Killer Dendritic Cells Have Antigen-Presenting Capacity during Influenza Virus Infection

Natural killer cells are innate effector cells known for their potential to produce interferon-γ and kill tumour and virus-infected cells. Recently, B220+CD11cintNK1.1+ NK cells were found to also have antigen-presenting capacity like dendritic cells (DC), hence their name interferon-producing killer DC (IKDC). Shortly after discovery, it has already been questioned if IKDC really represent a separate subset of NK cells or merely represent a state of activation. Despite similarities with DCs, in vivo evidence that they behave as bona fide APCs is lacking. Here, using a model of influenza infection, we found recruitment of both conventional B220− NK cells and IKDCs to the lung. To study antigen-presenting capacity of NK cell subsets and compare it to cDCs, all cell subsets were sorted from lungs of infected mice and co-cultured ex vivo with antigen specific T cells. Both IKDCs and conventional NK cells as well as cDCs presented virus-encoded antigen to CD8 T cells, whereas only cDCs presented to CD4 T cells. The absence of CD4 responses was predominantly due to a deficiency in MHCII processing, as preprocessed peptide antigen was presented equally well by cDCs and IKDCs. In vivo, the depletion of NK1.1-positive NK cells and IKDCs reduced the expansion of viral nucleoprotein-specific CD8 T cells in the lung and spleen, but did finally not affect viral clearance from the lung. In conclusion, we found evidence for APC function of lung NK cells during influenza infection, but this is a feature not exclusive to the IKDC subset.

A novel cell subset: Interferon-producing killer dendritic cells

Recent reports introduce a novel cell subset of DCs with antigenic phenotypes shared by both NK cells and B cells, but without surface markers of pDCs and T cells, appearing to be a chimera of NK cells and DCs, namely interferon-producing killer dendritic cells (IKDCs). IKDCs not only secret type I and type II interferons to recognize and kill tumor cells effectively, but also express MHC-II molecules to present antigens. Thus, IKDCs are considered as important immunosurveilance cells for tumors, providing a link between innate and adaptive immunity.

Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

The surface phenotype CD3-NK1.1+DX5+CD11c(int)B220+GR1- has been recently ascribed to a novel subset of mouse leukocytes termed interferon (IFN)-producing killer dendritic cells (IKDCs) that shares functions with natural killer (NK) cells and DCs. Interleukin-15 (IL-15) is critical for NK cells but its relationship with IKDC remained unexplored. An expression cassette encoding human IL-15 (hIL-15) has been transferred by hydrodynamic injection into the liver of mice, resulting in transient expression of the cytokine that is detectable during the first 48 h. hIL-15 hydrodynamic gene transfer resulted in an expansion of NK cells and IKDCs. Relative expansions of IKDCs were more dramatic in the IL-15 gene-transferred hepatic tissue than in the spleen. Adoptively transferred DX5+ cells comprising both NK cells and IKDCs proliferated in response to hydrodynamic injection of hIL-15, indicating that quantitative increases are at least in part the result of proliferation from already differentiated cells. Expansion is accompanied by enhanced cytolytic activity and increased expression of TRAIL and CD137 (4-1BB), without augmenting interferon-gamma production. The effects of a single hydrodynamic injection surpassed those of two intraperitoneal doses of the recombinant protein. The novel functional link between circulating IL-15 and IKDCs opens new possibilities to study the biology and applications of this minority cell subset.

Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells

Interferon-producing killer dendritic cells (IKDCs) have been described as possessing the lytic potential of NK cells and the antigen-presenting capacity of dendritic cells (DCs). In this study, we examine the lytic function and antigen-presenting capacity of mouse spleen IKDCs, including those found in DC preparations. IKDCs efficiently killed NK cell targets, without requiring additional activation stimuli. However, in our hands, when exposed to protein antigen or to MHC class II peptide, IKDCs induced little or no T cell proliferation relative to conventional DCs or plasmacytoid DCs, either before or after activation with CpG, or in several disease models. Certain developmental features indicated that IKDCs resembled NK cells more than DCs. IKDCs, like NK cells, did not express the transcription factor PU.1 and were absent from recombinase activating gene-2–null, common γ-chain–null (Rag2−/−Il2rg−/−) mice. When cultured with IL-15 and -18, IKDCs proliferated extensively, like NK cells. Under these conditions, a proportion of expanded IKDCs and NK cells expressed high levels of surface MHC class II. However, even such MHC class II+ IKDCs and NK cells induced poor T cell proliferative responses compared with DCs. Thus, IKDCs resemble NK cells functionally, and neither cell type could be induced to be effective antigen-presenting cells.

CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells

Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11cloB220+ cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207–213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214–219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor β (IL-2Rβ) chain but not those using the common γ chain (γc) are necessary for their generation. By directly comparing Rag2−/−γc −/y, Rag2−/−IL-2Rβ−/−, Rag2−/−IL-15−/−, and Rag2−/−IL-2−/− mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46+ cells are absent in Ncr1gfp/+γc −/y mice. Distinguishing features of IKDCs (CD11cloB220+MHC-II+) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220lo versus B220hi NK1.1+ NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1+ NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II+ NK1.1+ cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1+ cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11cloB220+ “IKDC-like” cells represent activated NK cells.

Interferon-γ is produced by another player of innate immune responses: The interferon-producing killer dendritic cell (IKDC)

Interferon-γ is a key cytokine in tumor immunosurveillance. The recently described interferon-producing killer dendritic cell (IKDC), can be distinguished from other innate effectors by its ability to kill a large variety of tumor cells and to produce high amounts of interferon-γ after encountering tumors in the absence of exogenous cytokines. The cytotoxic activity of IKDC was unraveled during an efficient immunotherapy combining c-kit tyrosine kinase inhibitors and interleukin-2, and is mediated through tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and interferon type IIR.

Ligation of TLR9 on lymphoid progenitors promotes dendritic cell production at the expense of lymphopoiesis (83.11)

Abstract Hematopoietic cells express TLR, raising the possibility that bacterial/viral products influence blood cell formation. We now show that common lymphoid progenitors (CLPs) express functional TLR9, and that dendritic cell production was strongly favored by TLR9 ligation with CpG ODN. TLR9 on CLPs rather than indirect cytokine mediated effects accounted for the shift in dendritic cell production, and CLPs became IL-7 unresponsive in culture. Similarly, CLPs from CpG treated mice had little ability to generate CD19+ cells and augmented competence to produce conventional (cDC), plasmacytoid (pDC) and interferon producing killer dendritic cells (IKDC) even in the absence of TNFα. Finally, lymphopoiesis in mice with active, but not latent HSV-1 infection was very similar to that seen in animals given CpG, and the changes were almost entirely mediated by TLR9. The findings bear on long standing controversies concerning the origins of dendritic cells and show how life-threatening infections may boost their production.