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Stem Cells 2003;21:357-362 www.StemCells.com
© 2003 AlphaMed Press

MEETING REPORT

A New Type I IFN-Mediated Pathway for the Rapid Differentiation of Monocytes into Highly Active Dendritic Cells

S.M. Santini, T. Di Pucchio, C. Lapenta, S. Parlato, M. Logozzi, F. Belardelli

Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy

Key Words. Dendritic cells • Type I IFN • APC • Vaccines

S.M. Santini, Ph.D., Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy. Telephone: 39-06-4990-3290; Fax: 39-06-4990-2097; e-mail: ssant{at}iss.it


   ABSTRACT
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 Abstract
Introduction
 Development and Functional...
 Conclusions
 References
 
Dendritic cells (DCs) are a unique leukocyte type consisting of different subsets of professional antigen-presenting cells. Since DCs initiate and govern the immune response, they represent an ideal target for intervention aimed at modulating and potentiating immune responses against cancer and infectious diseases. We recently described and characterized, at a functional level, a novel DC subset, interferon (IFN)-DCs, derived from blood monocytes after a short exposure to type I IFN and GM-CSF. Here, we review our recent studies on IFN-DCs and discuss their possible use in clinical immunotherapeutic strategies.


   INTRODUCTION
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 Abstract
 Introduction
Development and Functional...
 Conclusions
 References
 
Dendritic cells (DCs) are potent antigen-presenting cells (APCs) and play a central role in bridging innate and acquired immunity via direct cell-cell interactions and cytokine production [1–3]. Distinct DC populations and subsets can be distinguished in human peripheral blood on the basis of their relative expression levels of a series of surface markers: a major CD1a+/CD11c+ and CD1a-/CD11c+ population, expressing CD13, CD33, and the GM-CSF receptor (referred to as myeloid DCs), and a CD1a-/CD11c- population, expressing high levels of CD123 (interleukin-3R alpha [IL-3R{alpha}]), originally called lymphoid DCs and known as plasmacytoid DCs, which have been shown to constitute the major sources of type I interferon (IFN) upon virus challenge [4, 5]. Tissue-resident DCs are continuously replenished by extravasation of a pool of circulating immature DCs.

In recent years, DCs have been regarded as promising cellular adjuvants for the development of therapeutic vaccines against cancer and chronic viral infections. DCs can be manipulated and exposed to a variety of cytokines in vitro prior to reinfusion into patients. For research and clinical immunotherapeutic interventions, large numbers of immature DCs can be generated from blood monocytes cultivated for 5–7 days in the presence of GM-CSF and IL-4 [6]. GM-CSF appears to be required for in vitro monocyte survival and differentiation, while IL-4 has been shown to induce DC differentiation of human monocytes by exerting an inhibitory function on macrophage differentiation [7]. This procedure offers the advantages of a high yield and purity especially when the starting monocyte population is collected by leukapheresis. However, whether or not this treatment can reflect a natural pathway to DC generation is still a matter of debate. In particular, it is generally thought that such a pathway is unlikely to be operating in vivo, under physiologic conditions. In fact, while GM-CSF is secreted together with other factors by activated T cells and macrophages as well as by endothelial cells and fibroblasts upon exposure to inflammatory cytokines, high amounts of IL-4 are unlikely to be naturally produced under nonpathological conditions. In addition, DCs obtained from blood monocytes exposed to GM-CSF and IL-4 have been described to develop functional alterations, including altered in vivo migratory behavior [8]. Originally described for its antiviral activities, type I IFN has recently been shown to exert important effects on the immune system, including promotion of cellular and humoral responses, by virtue of its adjuvant effects on APCs [9–12]. As high amounts of IFN-{alpha} can be physiologically produced in response to infectious agents and inflammatory stimuli, especially by the so-called plasmacytoid DCs recently identified as the major source of type I IFN in vivo [4, 5], we focused our studies on this cytokine as a prototypic stimulus that could act as the natural factor inducing the differentiation of blood monocytes into potent APCs, acting as a potent danger signal.


   DEVELOPMENT AND FUNCTIONAL ACTIVITY OF DCS FROM BLOOD MONOCYTES EXPOSED TO TYPE I IFN
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Human CD14+ peripheral blood monocytes were obtained from healthy blood donors by standard Ficoll gradient centrifugation and subsequent enrichment by either Percoll gradient centrifugation or by negative selection with anti-CD3, anti-CD19, and anti-CD56 immunomagnetic beads, obtaining a purity greater than 98% [13]. The addition of IFN-{alpha} in conjunction with GM-CSF to blood monocytes resulted in the rapid loss of adherence to the substrate and the appearance of large cellular clusters. Within 3 days, IFN-exposed monocytes (IFN-DCs) developed very long and fine dendritic-like processes up to 21–30 µm in length, often ramified to form a sort of brush border at the protrusion periphery, which were characteristically and intensively stained by anti-CD44 antibodies (Fig. 1AGo). IFN-DCs often developed a cell-to-cell-associated polarity with axon-like protruding structures leading to cell-to-cell dot contact regions. In contrast, when examined at the same time point, IL-4-DCs appeared to maintain a substrate-associated polarity with evident adhesion plaques and exhibited squat and randomly distributed cell dendrites that did not show the unidirectional orientation typical of the IFN-DCs [14].



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  		Figure 1. A) Morphologic analysis and immunocytochemistry for CD44 expression in DCs generated in the presence of type I IFN. Monocytes were purified by standard Ficoll and 46% Percoll density gradient centrifugations, followed by positive immunomagnetic sorting (MACS Cell Isolation Kits; Miltenyi Biotec) for CD14+ cells (purity >95%). Monocytes were resuspended at a concentration of 2 x 106 cells/ml and exposed to 1,000 IU/ml of IFN-{alpha}n (natural IFN-{alpha}; Alfa-Wasserman) and 500 U/ml of GM-CSF (IFN-DCs) for 3 days. The photo shows the typical morphology of IFN-DCs. IFN-DCs were spun onto glass slides (Shandon; Cheshire, UK) at a concentration of 104 cells/ml, fixed with methanol (70%) for 10 minutes at +4°C, and stained by antibodies to CD44 (Dako; Denmark) using the peroxidase-anti-peroxidase (PAP/AEC) (Dako) method. Cells were counterstained with Mayer’s hematoxylin. Notably, the CD44 staining was typically localized on the thin and long dendrites. B) Phenotypic characteristics of DCs generated in the presence of type I IFN and GM-CSF. Monocytes were cultured in the presence of 1,000 IU/ml of IFN-{alpha}n (natural IFN-{alpha}; Alfa-Wasserman) and 500 U/ml of GM-CSF (IFN-DCs) for 3 days. After staining with fluorochrome-conjugated monoclonal antibodies to cellular membrane markers, the cells were analyzed by flow cytometry, electronically gating DCs according to light scatter properties in order to exclude contaminating lymphocytes and cell debris. Data were acquired and analyzed using a FACSort flow cytometer and Cell Quest software (Becton Dickinson). Dotted lines represent staining with isotype-matched control antibodies to an irrelevant antigen.

 
A 3-day exposure of blood monocytes to IFN-{alpha} resulted in a dramatic upregulation of HLA-DR and the costimulatory molecules CD80 and CD86 together with CD40 and the adhesion molecule ICAM-1 (CD54), consistent with differentiation of monocytes into DCs (Fig. 1BGo). Surprisingly, IFN-DCs displayed intermediate levels of CD123 expression, higher than those expressed by DCs from IL-4-treated monocytes, but lower than those expressed by plasmacytoid DCs. Despite the fact that the majority of IFN-DCs displayed features of immature DCs, markers of activated DCs, such as CD83 and CD25, appeared in variable percentages (12%–40%) of the cells together with very high levels of expression of costimulatory molecules.

Consistent with the appearance of these maturation markers, IFN-DCs expressed IL-15 mRNA [15] and released IL-15 in the culture supernatant without any further stimulus. We found that IFN-DCs were highly susceptible to conventional maturation stimuli and massively responded to tumor necrosis factor-alpha (TNF-{alpha}), lipopolysaccharide (LPS), and sCD40L, readily turning into activated/mature DCs [13].

IFN-DCs were found to markedly express the novel apoptosis-inducing molecule TRAIL (TNF-related apoptosis inducing ligand), which was virtually absent in the conventional IL-4/GM-CSF DCs unless activated by LPS treatment. As a consequence of TRAIL expression, IFN-DCs were also capable of specifically killing TRAIL-sensitive tumor cells [13]. In this regard, it is of interest to mention that both type I IFN and double-stranded RNA (poly I:C) [16] have been found recently to favor the acquisition of cytotoxic effector function by DCs, which can exhibit tumor cell killing activity [16–18] and may also play a role in the development of lymphopenia during the course of certain viral infections [19].

Different type I IFNs, including IFN-ß and natural IFN-{alpha} preparations, exerted similar effects on blood monocytes in the presence of GM-CSF, even though variable levels of expression of DC membrane markers were observed [13]. Notably, the addition of an IFN inducer, such as poly I:C double-stranded synthetic RNA, in conjunction with GM-CSF, mimicked the effect of exogenous type I IFN (our unpublished results). This suggests that IFN inducers, including viral infection or viral components, may be among the factors signaling danger to circulating monocytes, thus enabling them to rapidly differentiate into DCs.

The capacity of DCs to migrate to sites of inflammation and, subsequently, to local lymph nodes as well as their interaction with other immune cells is tightly regulated by the switch in the expression of different sets of chemokines and chemokine receptors. Initial response to inflammatory chemokines drives DC migration to peripheral tissues, while response to lymphoid-derived chemokines directs DC migration to secondary lymphoid tissues and their positioning within lymph nodes [20–22]. With respect to migratory behavior, IFN-DCs not only expressed very high levels of CC-chemokine receptor R5 (CCR5), but also displayed an enhanced migration in response to its ligands, the inflammatory chemokines regulated upon activation, normal T-cell expressed and secreted, macrophage inhibitory protein-1 alpha (MIP-1{alpha}), and especially MIP-1ß [14]. Consistent with their partially mature phenotype, a remarkable fraction of the IFN-DCs expressed CCR7 and exhibited a migratory response to MIP-3ß, a chemokine regulating DC trafficking to secondary lymphoid organs. Interestingly, IFN-DCs expressed considerable levels of the chemokine MIP-3ß, which has also been demonstrated to play an important role in chemoattraction of naïve T cells. When injected intravenously into severe combined immunodeficient (SCID) mice, IFN-DCs exhibited a greater migratory behavior than immature DCs generated in the presence of IL-4, rapidly localizing within mouse skin, as demonstrated by the detection of human DNA sequences by reverse transcription-polymerase chain reaction [14].

By virtue of their efficient antigen-processing machinery and high expression levels of molecules involved in antigen presentation and costimulatory activity, DCs play a central role in the generation of the primary immune response [1–3]; DCs capture and process incoming antigens in peripheral tissues and then migrate into regional lymph nodes, where they efficiently prime lymphocytes, promoting both cellular and humoral responses. In view of the characteristics of partially mature DCs, we hypothesized that IFN-DCs could exhibit a potent functional activity. In fact, IFN-DCs proved to be superior with respect to conventional monocyte-derived DCs in stimulating allogeneic mixed lymphocyte reaction (MLR), as assessed by 3H-thymidine incorporation assays, at very low stimulator/responder ratios, and in inducing IFN-{gamma} production, as evaluated by enzyme-linked immunosorbent assay of MLR culture supernatants [13]. On the other hand, as the ability to effectively prime naïve T cells and de novo immune response is a peculiar feature of professional APCs, as a second step, IFN-DCs were loaded with viral antigens. In vitro primary stimulation of autologous T cells with IFN-DCs pulsed with inactivated HIV virions was shown to induce vigorous lymphocyte proliferation and a T-helper type 1 polarized response, as revealed by the virtual absence of IL-4 in culture supernatant in the presence of high amounts of IFN-{gamma} after restimulation with antigen-pulsed DCs. As evidenced by Elispot assays, antigen presentation by IFN-DCs resulted in higher numbers of IFN-{gamma}-producing cells than did conventional immature DCs.

The promising results obtained in the in vitro experiments prompted us to evaluate the in vivo activity of DC-based vaccination in the human peripheral blood lymphocyte (PBL)-SCID mouse model [23–25]. SCID mice reconstituted with human PBLs were immunized according to a vaccination schedule involving repeated injection of autologous DCs pulsed with inactivated HIV. IFN-DC-based vaccination provided experimental evidence of greater human humoral response than that elicited by conventional immature monocyte-derived DCs toward the whole spectrum of HIV-1 proteins, with antibodies belonging mainly to the IgG1 isotype [13, 14]. Consistent with results obtained in vitro, a very high percentage of human CD8+ cells recovered from vaccinated xenochimeras exhibited a specific response toward HIV-1 antigens and conserved cytotoxic T lymphocyte (CTL) epitopes (manuscript in preparation).


   CONCLUSIONS
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 Development and Functional...
 Conclusions
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Recent studies indicate that type I IFN not only provides a first line of defense restricting viral replication, but can also act as an important factor linking innate and adaptive immunities, by inducing differentiation and activation of DCs [26]. Although the precise mechanism and the specific interplay between the type I IFN intracellular transduction pathway and DC differentiation have not yet been elucidated, it can be assumed that type I IFN exerts its functional activity on monocytes through the classical heterodimeric receptor composed of the IFNAR1 and IFNAR2 subunit [27], which activates a major signaling pathway involving the receptor-associated tyrosine kinases, Janus kinase type I (JAK1) and tyrosine kinase type 2 (Tyk2). These kinases phosphorylate a series of substrates including the signal transducer and activation of transcription (STAT) family transcription factors STAT-1 and STAT-2. Complex cooperation and interactions among the downstream effectors, induced by the JAK/STAT pathway, interferon regulatory factor, and probably NF-{kappa}B transcription factors, are probably involved in the change of monocytes into powerful antigen-presenting DCs.

IFN-driven DC differentiation from monocytes results in the impressive expression of costimulatory molecules and significant induction of activation/maturation markers (Figs. 1Go and 2Go). Interestingly, it has been recognized that many of the stimuli promoting DC maturation also induce the production of type I IFN, suggesting an autocrine/ paracrine IFN-induced cytokine loop or a direct role of type I IFN, in cooperation with other cytokines, in the induction of DC maturation. Results obtained in other experimental models have shown that type I IFN treatment promotes the expression of costimulatory and HLA molecules but fails to induce terminal maturation [28, 29]. Notably, exposure to IFN-{alpha} also has been described to promote the maturation of blood CD11c myeloid DCs [30] and to enhance CD40 ligand-mediated activation of monocyte-derived DCs [31] as well as the terminal maturation of CD34+-derived DCs [32]. However, recent data suggest that responsiveness to type I IFN is tightly regulated and finally lost during terminal maturation of monocyte-derived human DCs [33].



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  		Figure 2. Schematic representation of the development and functional activity of IFN-DCs. The figure summarizes both the in vitro and the hypothetical in vivo generation of DCs by exposure of blood monocytes to high levels of type I IFN.

 
Immunity induced by vaccination depends on the efficacy of antigen presentation. In particular, DCs loaded with tumor antigens, peptides, or tumor cell lysates represent an ideal tool for efficient sensitization of the immune system, with important potential applications in cancer immunotherapy to be combined with conventional cancer treatment [34, 35]. The encouraging results in vaccination studies in animal models and the development of protocols for generating large numbers of human DCs have recently led to the start of clinical trials aimed at verifying the efficacy of DCs as cellular adjuvants in oncologic patients. In current practice, peripheral blood monocytes cultured in the presence of IL-4 and GM-CSF for 5–7 days represent the most common source of in vitro-generated DCs. Exposure to a series of stimuli, including TNF-{alpha}, LPS, and CD40L for an additional 1–2 days is generally needed to obtain terminal maturation of such DCs, which are induced to express high levels of costimulatory molecules and to acquire de novo expression of the maturation marker CD83. We recently provided evidence suggesting that blood monocytes represent a circulating pool of DC precursors capable of rapidly differentiating into highly active DCs in response to soluble mediators. Type I IFN could act as a danger signal enabling monocytes to interface natural response with adaptive immunity (Fig. 2Go). These results could have important practical applications. In the field of immunotherapeutic strategies, the generation of IFN-DCs may exhibit some advantages that can be summarized as follows: short-term cultivation, a higher expression of molecules involved in antigen presentation, appearance of a mature phenotype in a significant proportion of cells without adding additional factors, and efficient stimulation of both the humoral and cellular arm of the immune response. We believe that this novel type of DC deserves further attention to explore its use in clinical protocols. Future research efforts will uncover the natural mechanisms governing DC differentiation from monocytes providing new insights for in vitro production of DCs for designing novel immunotherapy protocols for the treatment of some chronic infections and malignant diseases.


   ACKNOWLEDGMENT
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 Development and Functional...
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Work in the authors’ laboratory was supported in part by grants from the Italian Association for Cancer Research (Milan) and the Italian Ministry of Health.


   REFERENCES
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Received September 16, 2002; accepted for publication December 8, 2002.



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