Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.0903446 on January 2, 2004

Published online before print January 2, 2004
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(Journal of Leukocyte Biology. 2004;75:600-603.)
© 2004 by Society for Leukocyte Biology

Limitations with in vitro production of dendritic cells using cytokines

Helen C. O’Neill1 and Heather L. Wilson

School of Biochemistry and Molecular Biology, Faculty of Science, Australian National University, Canberra

1Correspondence: School of Biochemistry and Molecular Biology, Building #41, Linnaeus Way, Australian National University, Canberra, ACT 0200, Australia. E-mail: Helen.ONeill{at}anu.edu.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 DC PRECURSOR POPULATIONS
 IN VITRO PROTOCOLS FOR...
 SPECIFICITY OF CYTOKINE EFFECTS
 CONCLUSIONS
 REFERENCES
 
Dendritic cells (DC) are the most effective antigen-presenting cells. Many studies now show that DC can be generated in vitro from a number of starting cell populations containing hematopoietic precursors. The protocols used involve different combinations of cytokines including granulocyte macrophage-colony stimulating factor (GM-CSF), which supports myeloid precursors, or interleukin-7, which supports lymphoid precursors. DC are commonly generated by in vitro culture of bone marrow or monocytes with GM-CSF and other cytokines. However, these cultures do not sustain DC production for long periods of time and do not allow the identification or study of intermediate stages in cell development. In vitro cytokine-dependent cultures of DC precursors do provide a reliable source of DC for stimulating immune responses. However, use of cells produced in cytokine-dependent cultures for the study of DC differentiation is limited, as DC development in vivo differs in cytokine dependency.

Key Words: hematopoiesis • differentiation • GM-CSF


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
DC PRECURSOR POPULATIONS
 IN VITRO PROTOCOLS FOR...
 SPECIFICITY OF CYTOKINE EFFECTS
 CONCLUSIONS
 REFERENCES
 
The dendritic cell (DC) lineage is characterized by a number of phenotypically distinct DC subsets with particular tissue distribution and function. Despite extensive investigations on DC biology, the lineage origin of DC is still not clear and is a very controversial area. Most peripheral DC appear to be myeloid lineage cells. There is also evidence in humans and mice that some DC, including thymic DC and plasmacytoid DC in thymus and spleen, are derived from lymphoid lineage precursors [1 ]. DC represent a trace population of cells in vivo and are extremely difficult to isolate for study. They are commonly generated in vitro from isolated progenitor cells cultured in a cocktail of cytokines.

Granulocyte macrophage-colony stimulating factor (GM-CSF) has been the most commonly used cytokine for in vitro expansion of DC. Initially, GM-CSF was shown to enhance survival and differentiation of major histocompatibility complex (MHC) class II+ blood DC for up to 6 weeks of culture [2 ]. However, after it was found that mature MHC class II+ DC could not divide [3 ], amplification of DC numbers was then achieved by culture of MHC class II− precursors from mouse blood [4 ] or bone marrow (BM) [5 ]. This precursor population was found to replicate in medium supplemented with GM-CSF. However, GM-CSF-supported cultures did not generate a pure population of cells, and granulocytes and macrophages were produced in addition to mature DC. The early stages of culture were characterized by aggregates of DC affixed to a stromal monolayer comprising macrophages and fibroblasts [4 , 5 ]. Early events in DC development appear to be stromal cell-dependent [6 , 7 ], suggesting that stromal cell-derived cytokines, in addition to GM-CSF, may be important in DC development. DC generated in cytokine-supplemented cultures in vitro survive for only a limited period of time. These cultures do not support the proliferation of progenitor cells, and so cultures are not replenished by newly differentiating DC. Subsequent studies have attempted to more completely define cytokine requirements for DC development from precursors.


   DC PRECURSOR POPULATIONS
TOP
 ABSTRACT
 INTRODUCTION
 DC PRECURSOR POPULATIONS
IN VITRO PROTOCOLS FOR...
 SPECIFICITY OF CYTOKINE EFFECTS
 CONCLUSIONS
 REFERENCES
 
Production of highly pure populations of DC has been achieved using in vitro culture systems that use a defined starting cell population. Several different precursor cell subsets have been identified, and each has been shown to have distinct cytokine requirements for DC production. These include lineage-negative (Lin−) CD117+ subsets from BM and fetal liver [8 , 9 ], peripheral blood monocytes [10 ], and "CD4 low" cells in the thymus [11 ]. Progeny DC have also been derived from purified, primitive, self-renewing hematopoietic stem cells as well as lineage-restricted common lymphoid precursors (CLP), common myeloid precursors (CMP), granulocyte/macrophage-restricted precursors, and pro-T cells [12 ]. Caution must be applied when using these findings to identify the lineage origin of DC because of continuing uncertainty about the differentiative potential of precursor subsets such as the CLP [13 ].

Despite increased definition of hematopoietic cell subsets, there is still no clear definition of a DC progenitor. As DC subsets derive from a range of different tissues, it is still not possible to distinguish one or multiple DC progenitors giving rise to distinct DC lineages. Recently, the fetal liver tyrosine kinase 3 (Flt3)+ murine BM population, which includes CMP and CLP, has been shown to contain precursors of all lineages of DC including plasmacytoid DC [14 ]. Two distinct DC precursor populations have been identified in mouse blood, which resemble those in humans [15 ]. One represents a precursor of myeloid DC, and the other resembles a plasmacytoid DC precursor marked by CD45RA and CD8{alpha} expression. Evidence for a committed precursor of CD8{alpha}+ DC has been confirmed by identification of a precursor population of CD8{alpha}+CD11c−Lin− cells in spleen and other lymphoid tissues, which generates CD8{alpha}+CD11c+ DC in vivo [16 ].

Most cytokine-supplemented in vitro cultures drive progenitors quickly through to mature DC, preventing the characterization of intermediate precursors. However, some of these culture systems use a set of specific cytokines to support an initial phase of proliferation, producing "immature DC", followed by a second phase of culture with a different set of cytokines to induce complete DC maturation [8 , 17 , 18 ]. These are identified in Figure 1 . However, most DC generated in cytokine-supported in vitro cultures resemble mature DC on the basis of expression of MHC class II and the CD80/CD86 costimulatory molecules, as well as capacity for T cell stimulation. Subsets of CD8{alpha}+ and CD8{alpha}− DC have also been detected. The immature DC stage has been bypassed in these cultures. Some intermediate or immature DC can be identified by retention of capacity to form macrophages when exposed to mediators such as M-CSF [11 , 19 ]. Bipotential cells appear to represent intermediate precursors rather than fully differentiated but immature DC. Figure 1 summarizes the in vitro culture systems commonly used to generate DC from various progenitor populations. Stages in DC development in Figure 1 are indicated as precursor or mature, based on the above rationale.



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  		Figure 1. Cytokine-dependent cultures used to generate DC. Precursor populations, intermediate cells, and mature DC are indicated. Starting populations include Lin− BM, peripheral blood mononuclear cells (PBMC), Lin−CD117+ BM, thymic CD4 low precursors, CLP, and CMP. Cytokine combinations used for culture are shown. IL, Interleukin; TNF-{alpha}, tumor necrosis factor {alpha}; SCF, stem cell factor; TGF-ß, transforming growth factor-ß; Flt3L, Flt3 ligand; IFN-{alpha}, interferon-{alpha}; LPS, lipopolysaccharide; mAb, monoclonal antibody.

 

   IN VITRO PROTOCOLS FOR DC GENERATION
TOP
 ABSTRACT
 INTRODUCTION
 DC PRECURSOR POPULATIONS
 IN VITRO PROTOCOLS FOR...
SPECIFICITY OF CYTOKINE EFFECTS
 CONCLUSIONS
 REFERENCES
 
Culture of monocytes or BM cells with GM-CSF, TNF-{alpha}, and IL-4 or SCF represents the most common procedure used to derive DC in vitro. Mouse PBMC and Lin− BM cells can be induced to become MHC class II+ mature DC if cultured with a combination of GM-CSF and IL-4 [10 ] (Fig. 1A) . In some cultures, TNF-{alpha} is added to induce further activation [17 ]. Used alone, TNF-{alpha} provides no growth promotion for hematopoietic progenitor cells (HPC) but assists in the development of mature DC [20 ]. By comparison, IL-4 maintains DC in a more immature state, capable of antigen capture and processing [21 ].

SCF was incorporated into in vitro culture systems after it was shown to increase DC yield from human CD34+ HPC [22 ]. When cultured with SCF in combination with GM-CSF and TNF-{alpha}, Lin−CD117+ BM cells proliferate and develop into two distinct dendritic precursor populations [8 ] (Fig. 1B) . In a second period of nonproliferative differentiation, GM-CSF and TNF-{alpha} can be used to generate mature Langerhans cells (LC) from CD11bloCD11c+ DC precursors or mature DC from bipotent CD11bhiCD11c+ myeloid precursors. Similar mature DC can be generated from human CD34+ HPC using GM-CSF and TNF-{alpha} [23 ].

TGF-ß has a specific role in LC development. It is essential for the differentiation of LC in vivo [24 ] and has been used in combination with GM-CSF, SCF, and TNF-{alpha} to generate LC in vitro from Lin−CD117+ BM cells [18 ] (Fig. 1C) . TGF-ß appears to be effective in DC production in vitro only when TNF-{alpha} is also present; otherwise, it inhibits DC production [25 ]. Flt3L can be used to expand DC numbers in vivo [26 ], although it does not act specifically on DC. When injected into mice, it expands many hematopoietic cell types, including lymphocytes, natural killer cells, erythroid cells, monocytes, and granulocytes [27 , 28 ]. Flt3L can generate the CD8{alpha}− and CD8{alpha}+ DC subsets in vitro from Lin− BM. Mature CD11bhiCD11c+ and CD11bloCD11c+ intermediate DC subsets are activated with IFN-{alpha} or LPS to give these two distinct subsets [29 ] (Fig. 1D) . However, Flt3L is not solely responsible for the development of DC from Lin− BM cells, as DC grow in these cultures from aggregates associated with adherent macrophages, and endogenously produced IL-6 is also important in their development [29 ].


   SPECIFICITY OF CYTOKINE EFFECTS
TOP
 ABSTRACT
 INTRODUCTION
 DC PRECURSOR POPULATIONS
 IN VITRO PROTOCOLS FOR...
 SPECIFICITY OF CYTOKINE EFFECTS
CONCLUSIONS
 REFERENCES
 
There is now evidence to suggest that GM-CSF is essential for the development of myeloid lineage DC. CMP in BM require GM-CSF as well as other cytokines for DC production [12 ] (Fig. 1E) . Lymphoid lineage DC have been shown to have different cytokine requirements. For example, colonies of thymic DC can be generated by culture of CD4 low thymic precursor cells in a cocktail of seven growth factors including IL-1ß, TNF-{alpha}, IL-3, IL-7, SCF, Flt3L, and anti-CD40 mAb [30 ] (Fig. 1F) . IL-7, not GM-CSF, was found to be the essential factor for development of thymic DC, and cells produced are functional mature DC. However, in contrast to normal lymphoid DC in thymus, which express CD8{alpha} and BP-1, in vitro-grown cells do not express these specific markers, suggesting that the culture may not exactly mimic in vivo conditions for thymic DC development [30 ]. Consistent with this finding is evidence that IL-7, not GM-CSF, is the essential cytokine for the generation of DC from CLP in BM [12 ] (Fig. 1G) . These combined studies confirm that various cell subsets containing myeloid, lymphoid, or plasmacytoid DC progenitors have different cytokine requirements for generation of DC.

Recently, the Flt3 receptor was identified as a specific marker for progenitor cell subsets that produce DC of all lineages upon in vivo transfer into mice [31 , 32 ]. This suggests a central role for Flt3L in early DC differentiation. Figure 1 identifies many examples of progenitor cell subsets, which respond to Flt3L as well as GM-CSF when cultured in vitro. It is well known, however, that GM-CSF is not essential for DC development in vivo, as DC develop independently of GM-CSF in GM-CSF−/− mice and in mice overexpressing GM-CSF [33 ]. In the specific case of DC developing from progenitors in long-term stroma-dependent cultures, DC development also occurs independently of GM-CSF [34 ]. All evidence presented in Figure 1 identifies GM-CSF as an essential cytokine for production of myeloid DC from progenitors in vitro. It also identifies the production of only mature or activated DC in GM-CSF-supported cultures. One argument is that Flt3L may be a central cytokine for early DC development in vivo except during inflammatory situations when GM-CSF may be important [32 ]. One explanation for the central role of GM-CSF in DC development in vitro is that the culture of DC precursors directly on plastic surfaces may deliver an activation signal to cells, making them responsive to GM-CSF and other inflammatory cytokines, leading to the proliferation and maturation of DC in these cultures [35 ]. The importance of inflammatory cytokines and chemokines in DC development has been confirmed in vivo. DC precursors enter inflammatory lesions in the liver, where they have been seen to undergo maturation and then to migrate into lymphoid sites for T cell interaction [36 ]. Although this process involves myeloid DC, the role of plasmacytoid DC is not yet confirmed.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 DC PRECURSOR POPULATIONS
 IN VITRO PROTOCOLS FOR...
 SPECIFICITY OF CYTOKINE EFFECTS
 CONCLUSIONS
REFERENCES
 
Cytokine supplementation can be used to generate high numbers of DC in vitro for experimentation. These studies have contributed, to some extent, to our knowledge of DC development and maturation as well as lineage commitment. However, a number of limitations are associated with the use of cytokines to induce DC proliferation in vitro. Cytokines are used in concentrations higher than would be expected in vivo and could direct development along pathways that are not physiologically normal. For example, in vitro cultures of DC precursors have been shown to respond to GM-CSF, which is not an essential cytokine for normal DC differentiation in vivo. Furthermore, lymphoid-lineage, thymic DC, derived by in vitro culture, lack CD8{alpha} marker expression, in comparison with their ex vivo counterparts. This identifies CD8{alpha} as an unreliable marker for this DC subset. The purity of DC produced in these cultures is also questionable, and cultures could contain DC in different stages of development or other unknown contaminant cell types. A further important factor is that DC produced from different starting cell populations, such as monocytes and BM or cord blood HPC, can vary in their functional capacity [10 , 37 , 38 ]. The fact that precursor cells derived from different tissues and stimulated by different cytokine cocktails can generate different types of DC is an important consideration when preparing DC populations for study or use as an immunotherapeutic tool.

Received September 28, 2003; revised October 23, 2003; accepted October 24, 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 DC PRECURSOR POPULATIONS
 IN VITRO PROTOCOLS FOR...
 SPECIFICITY OF CYTOKINE EFFECTS
 CONCLUSIONS
 REFERENCES
 

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