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(Journal of Leukocyte Biology. 2001;69:11-20.)
© 2001 by Society for Leukocyte Biology

Heterogeneity of human peripheral blood monocyte subsets

E. Grage-Griebenow*, H.-D. Flad{dagger} and M. Ernst{dagger}

* Experimental Pneumology, Ruhr-University Bochum
{dagger} Immunology and Cell Biology, Research Center Borstel, Germany

Correspondence: E. Grage-Griebenow, Bergmannsheil-Clinic of the Ruhr-University Bochum, Experimental Pneumology, BGFA XU-19, Bürkle-de-la-Camp-Platz-1, 44789 Bochum, Germany. E-mail: evelin.grage-griebenow{at}ruhr-uni-bochum.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MO SUBSETS AS DEFINED...
 MO SUBSETS AS DEFINED...
 MO SUBSETS AND THEIR...
 MO SUBSETS IN PATHOPHYSIOLOGICAL...
 DEVELOPMENTAL HISTORY OF MO...
 CONCLUDING REMARKS ON THE...
 REFERENCES
 
In recent years the number of reports describing phenotypically and functionally distinct subsets of human blood leukocytes, and in particular of subtypes of antigen-presenting cells has continuously increased. A great diversity was described not only for dendritic cells (DC), but also for human blood monocytes (Mo) and macrophages (Mac). Similar to DC, the different types of Mo subsets could be defined by distinct phenotypes and immunoregulatory functions. The characterization of blood Mo subpopulations revealed that some of them exhibit common features with myeloid or lymphoid DC and tissue Mac, but also demonstrate the existence of novel unique cell populations. The generation of lymphoid and myeloid DC and their heterogeneity has been the subject of recent reviews. Here we focus on Mo from human peripheral blood and summarize the data (including our own) dealing with their phenotypic and functional, in particular immunoregulatory properties.

Key Words: dendritic cells • lymphoid cells


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MO SUBSETS AS DEFINED...
 MO SUBSETS AS DEFINED...
 MO SUBSETS AND THEIR...
 MO SUBSETS IN PATHOPHYSIOLOGICAL...
 DEVELOPMENTAL HISTORY OF MO...
 CONCLUDING REMARKS ON THE...
 REFERENCES
 
Mo are members of the human mononuclear phagocyte system, which is important for the nonspecific defense against pathogenic organisms and tumor surveillance, and which exerts immunoregulatory functions like accessory activities and cytokine production. In recent years it has been described that Mo themselves consist of further cellular subtypes that are heterogeneous in phenotype and function. Mo are generated from CD34+ myeloid progenitors, a feature they share with erythrocytes and thrombocytes. Upstream in the myeloid lineage there exists a myelodendritic progenitor cell from which Mo as well as granulocytes and CD14-derived DC [1 ] are generated. Recent publications indicate that CD34+ precursors that express Mac colony-stimulating factor receptor (M-CSF-R) and/or Fc{gamma}-receptor-I (CD64) give rise exclusively to myelomonocytic cells. Both receptors are not found on early erythroid or lymphoid precursors. Furthermore, CFU-GM and immature myeloid monocytic precursors in bone marrow or cord blood are characterized by high expression of the class III receptor tyrosine kinase FLT3 (CD135) [2 ]. In peripheral blood one finds mature Mo and granulocytes but also precursor cells like CD34+ progenitor cells [3 , 4 ] that may undergo further differentiation depending on the local environment. During tissue damage and infection, components of pathogens, cytokines, chemokines, etc. are produced and deliver activation signals for the recruitment of different leukocytes to the inflammatory site. Mo receiving such a stimulus enter the inflamed tissue and differentiate into Mac, a process associated with functional alterations [5 , 6 ]. Phenotypical and functional heterogeneity has also been described for tissue Mac [7 ]. In this review, however, we will focus on the phenotypical and functional characterization of Mo and their subsets isolated from human peripheral blood.


   MO SUBSETS AS DEFINED BY SIZE AND DENSITY
TOP
 ABSTRACT
 INTRODUCTION
 MO SUBSETS AS DEFINED...
MO SUBSETS AS DEFINED...
 MO SUBSETS AND THEIR...
 MO SUBSETS IN PATHOPHYSIOLOGICAL...
 DEVELOPMENTAL HISTORY OF MO...
 CONCLUDING REMARKS ON THE...
 REFERENCES
 
Almost 20 years ago it was shown that human peripheral blood Mo are not a homogeneous population, but differ in their phenotype and function, and the parameters for defining Mo subsets and the separation techniques are numerous.

In the earliest isolation procedures for different Mo subsets gradient centrifugation and counterflow centrifugation (elutriation) were used, which allowed the separation of Mo subsets by size and density. Employing these techniques, most of the authors distinguished between two main subsets. Thus, Akiyama et al. defined a major population of so-called "regular Mo" and a minor subset of "intermediate Mo" [8 , 9 ]. The regular Mo were characterized by larger size and higher expression of the Mo-specific surface antigen OKM1 and exhibited higher peroxidase activity, higher accessory capacity in mitogen-induced T cell proliferation, and higher antibody-dependent cell-mediated cytotoxicity (ADCC) than intermediate Mo. In contrast, the intermediate Mo could be more easily mobilized from extravascular reservoirs. Differences were also found with regard to Poly(I:C)-induced cytokine release. The regular Mo released a greater amount of interleukin-1 (IL-1), colony-stimulating factor (CSF), and prostaglandin E2 (PGE2) than intermediate Mo, which were found to produce more interferon-{alpha} (IFN-{alpha}). Similar to the definition of regular Mo and intermediate Mo [8 9 10 ] Weiner et al. [11 ] identified a population of larger cells with higher myeloperoxidase (MPO) activity, higher superoxide production in response to zymosan, and higher CSF-producing capacity [10 ] compared to a subset of small cells with high cytotoxicity toward heterologous tumors [11 ]. In addition, Figdor et al. [12 ] described a high-density, esterase-positive Mo fraction with high peroxidase activity, ADCC, and high accessory activity in mixed leukocyte reaction (MLR) compared with low-density Mo. Furthermore, different Mo subsets with regard to cytokine production were reported [13 , 14 ], showing that Mo of high-density fractions from Percoll-gradient preparations released more IL-1 than cells of low-density fractions [13 ], and that the IFN-{alpha}-producing capacity was higher in HLA-DR+ nonadherent cells of low-density fractions [14 ].

In contrast to Akiyama [8 , 9 ] reporting comparable phagocytic activity, HLA-DR-expression, and Fc{gamma}-receptor (Fc{gamma}R) expression for regular and intermediate Mo, other authors associated high phagocytic activity with the fraction of high density and low phagocytic activity with the less dense elutriation-derived Mo fraction [15 ]. Furthermore, Fernandez [14 ] reported higher HLA-DR expression for less-dense cells, and Schreiber [16 ] associated high expression of Fc{gamma}R and C3 complement receptor with the high-density population. Differences between Mo subsets were also described for their chemotactic activity, which was found to be higher in large Mo than in small Mo [17 ]. Besides the dissociation in accessory capacities in MLR and supportive capacity in mitogen-induced B cell differentiation, differences in their function as antigen-presenting cells (APC) were demonstrated [18 ]. The smaller subset was found to efficiently present soluble tetanus toxoid (TT) and particulate (cytomegalovirus-infected fibroblast) antigens, whereas the larger subset of strongly CD14+-expressing cells exhibited low antigen-presenting capacity, but high activity in suppression of lymphocyte function. Taken together, in these earlier studies two phenotypically and functionally different monocyte subsets were distinguished: A major subset of large, high-density, CD14+/Fc{gamma}R+ (also) monocytes exhibiting phagocytic activity, high production of cytokines and reactive oxygen species, high ADCC and suppressor activity for antigen-activated lymphocytes, and a small subset of less dense, loosely adherent HLA-DR+ cells with high IFN-{alpha}-producing capacity and exhibiting potent APC capacity.


   MO SUBSETS AS DEFINED BY THEIR SURFACE ANTIGEN CHARACTERISTICS
TOP
 ABSTRACT
 INTRODUCTION
 MO SUBSETS AS DEFINED...
 MO SUBSETS AS DEFINED...
MO SUBSETS AND THEIR...
 MO SUBSETS IN PATHOPHYSIOLOGICAL...
 DEVELOPMENTAL HISTORY OF MO...
 CONCLUDING REMARKS ON THE...
 REFERENCES
 
In more recent studies, definition of Mo subsets was mainly based on their differences in surface marker expression (Table 1 ) In most of the studies Mo subsets were first phenotypically discriminated by their differential expression of Fc{gamma}R alone or in combination with other surface markers and functions. Mo expressing Fc{gamma}R-I and -II, but not Mo expressing Fc{gamma}R-III, were reported to efficiently mediate ADCC [19 ]. Early isolation procedures for the separation of Fc{gamma}R+ and Fc{gamma}R- Mo were based on the ability to form rosettes with human IgG anti-D antibody-coated human erythrocytes [0,Rh 0(D)+] and subsequent density gradient centrifugation and adherence to plastic [20 21 22 23 24 25 26 27 ]. Although binding of monomeric IgG to Fc{gamma}R of Mo is mainly mediated by Fc{gamma}R-I [28 ], Fc{gamma}R-II and -III can also engage in rosette formation [29 ]. Therefore, in later studies immunofluorescence labeling with Fc{gamma}R-specific Ab and flow cytometric cell sorting for the exact definition and separation of Mo subsets were employed [19 , 28 , 30 , 31 ]. Fc{gamma}R-I was found on the majority of Mo. Similar to the regular Mo described above [8 , 9 , 15 ], these cells were described to be larger than Fc{gamma}R-I- cells, to represent potent phagocytes [30 , 32 ], and to produce higher amounts of proinflammatory cytokines like IL-1, IL-6, tumor necrosis factor {alpha} (TNF-{alpha}) [20 , 33 ], and also higher amounts of PGE2 [20 ], known to suppress APC function and T cell activity [25 26 27 ]. This subset was found to also suppress PWM or Staphylococcus aureus-stimulated immunoglobulin release [22 ] independent of activation of T suppressor cells [23 ]. In line with the finding that large Mo display higher chemotactic activity than small Mo [17 ], the Fc{gamma}R+ Mo were defined as the main population expressing receptors for C5a and N-formyl-methionyl-leucyl-phenylalanine (fMLP) [34 ]. Similar to the less-dense Mo described above [8 , 9 , 18 ], Fc{gamma}R-I- Mo appeared to be small monocytes, exhibiting high IFN-{alpha}-producing capacity [30 , 35 ] and high accessory capacity for antigen (PPD and influenza A antigen)-driven T cell activation compared to regular or Fc{gamma}R-I+ Mo [25 26 27 , 30 , 35 , 36 ]. In addition, Fc{gamma}R- Mo were found to be better producers of plasminogen activator correlating with higher APC function for TT [20 ]. Fc{gamma}R- Mo appeared to be mainly responsible for the induction of nonspecific inhibitory factor (ncINH) in T cells activated by purified polysaccharide extract from Candida albicans (MPPS) [37 ]. Fc{gamma}R- Mo were further characterized by exhibiting low cytostatic effects against tumors [26 , 27 ], showing high expression of MHC class I and II [30 ], high accessory capacity in mitogen (PWM)-, antigen (PPD)-induced, and alloantigen-induced T cell activation [25 26 27 , 30 ]. Therefore, T cell activation was clearly associated with the smaller Fc{gamma}R-I- Mo and not with Fc{gamma}R+ or regular Mo as described before [8 , 9 , 12 ]. Recently, Fc{gamma}R-I- Mo were also found more resistant to killing by antigen-activated CD4+ T cells and to CD95 (Fas)-mediated cell death [36 ], compared to Fc{gamma}R-I+ cells, which might be the reason for their enhanced T cell accessory capacity. In summary, these data indicate that separation of Mo based on size and density results in subsets that share features with subsets defined by Fc{gamma}R expression but are not identical.


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  		Table 1. Phenotypic and Functional Properties of Human Blood Monocyte Subsets

 
In contrast to Fc{gamma}R-I (CD64), Fc{gamma}R-III (CD16) was found to be expressed only on a small subset of Mo, and several authors also described phenotypical and functional differences for those Mo that express or lack Fc{gamma}R-III. Studies of Ziegler-Heitbrock et al. [38 , 39 ] revealed different functions between Mo expressing or lacking Fc{gamma}R-III. Accordingly, the majority of Mo appeared as CD14+/CD16- low HLA-DR-expressing phagocytic cells with high producing capacity for reactive oxygen radicals and proinflammatory cytokines, features they share with Fc{gamma}R-I+ Mo (Table 1) . In addition, there exists a minor subset of CD14dim/CD16+ cells with bright expression of HLA-DR and low cytokine production [38 , 39 ], characteristics that are also described for Fc{gamma}R-I- Mo [30 ] and alveolar Macs [39 , 40 ]. Furthermore, regular CD14+/16- and the minor CD14dim/CD16+ subsets differ in the expression of the scavenger receptor and receptor-mediated binding of low-density lipoprotien (LDL) [41 ]. CD14+/CD16- cells exhibit higher expression of Sc-receptor class A type I/II and also stronger LDL binding than CD14dim/CD16+ cells. Very recent studies reported that CD14dim/CD16+ cells exhibit high expression of ILT4 [42 ], a member of the recently described immunoglobulin-like receptor family of immune regulators. Furthermore, other authors differentiate between a larger CD14+/CD16- subset with high accessory capacity for polyclonal (CD3)-activated T cells and a smaller less efficient CD14dim/CD16+ subset [43 ]. A very recent study also revealed differences in the chemokine receptor expression and chemotactic activity of these subsets. CD14+/CD16- cells show expression of CCR2 that is paralleled with higher chemotactic migration responsiveness for monocyte chemotactic protein-1, whereas CD14dim/CD16+ cells lack the expression of CCR2 but show higher expression of CCR5 and migrate in response to macrophage inflammatory protein-1{alpha}/RANTES [44 ]. Finally, our recent studies on Mo subsets [45 ] as defined by immunofluorescence double labeling with anti-CD64 and anti-CD16 mAb revealed that Fc{gamma}R-I+ and Fc{gamma}R-I- Mo subsets could be further divided into four phenotypically and functionally different subsets, as also demonstrated in Table 1 . The minor subset of Fc{gamma}R-I- Mo itself consists of a CD64-/CD16- and a CD64-/CD16+ cell population. The double-negative subset was lineage-negative, appeared as small, less granular cells in flow cytometry, and was characterized by low accessory activity but high IFN-{alpha} release in response to viruses (NDV, Sendai, influenza type A antigens), a function they have in common with the natural IFN-{alpha}-producing cells described by Sandberg [46 , 47 ] and Svennson [48 ]. The CD64-/CD16+ subset is phenotypically closely related to the CD14dim/CD16+ subset of Mo or Mac-like cells, as defined by Ziegler-Heitbrock [38 39 40 ]. It also shares some phenotypical features with the CD14dim/CD16+ Mo population described by Thomas [43 ], since both show high expression of HLA-DR, but diminished expression of CD14, CD33, and CD64, and exhibit Mo morphology. But the finding that the latter are of low accessory capacity in TT-induced T cell responses [43 ], whereas CD64-/CD16+ are highly efficient in presenting antigens (PPD and viral) to autologous T cells [45 ] indicates that these populations are not identical. Within the Fc{gamma}R-I+ Mo one could also distinguish between two subsets. The major subset, expressing CD64 but not CD16, represents typical phagocytically active Mo with high expression of Mo-specific cell markers CD14 and nonspecific esterase, but exhibiting low T cell accessory activity [32, 45]. Furthermore, a novel minor subset of CD64+/CD16+ with unique characteristics could be identified [45 ]. This population combines typical mature DC characteristics [49 ] like high IL-12 production, high T cell accessory capacity, high expression of HLA-DR, costimulatory CD86, and CD11c with typical Mo features such as monocytic morphology, high expression of CD14, and high phagocytic activity [32, 45]. These data indicate that differential function within Mo is not only associated with differential Fc{gamma}R expression but is also often combined with further differences in other surface markers such as CD14 or HLA-DR. In this context, high expression of HLA-DR seems to be also combined with high expression of HLA-DQ, since HLA-DRhigh/DQhigh Mo are more potent in presenting mumps or TT antigens to autologous T cells than HLA-DRlow/DQlow Mo [50 ]. Differences in the cytokine production and APC activity were also described for Mo as defined by CD4 expression. High PGE2 production and low antigen-presenting capacity was more associated with CD4- than with CD4+ Mo [21 ].


   MO SUBSETS AND THEIR RELATION TO OTHER CELL TYPES IN BLOOD AND TISSUE
TOP
 ABSTRACT
 INTRODUCTION
 MO SUBSETS AS DEFINED...
 MO SUBSETS AS DEFINED...
 MO SUBSETS AND THEIR...
MO SUBSETS IN PATHOPHYSIOLOGICAL...
 DEVELOPMENTAL HISTORY OF MO...
 CONCLUDING REMARKS ON THE...
 REFERENCES
 
From the above description it has become evident that the heterogeneity of blood Mo is enormous and comparable to that described for DC. A comparison of the specific features that defined the different Mo subsets revealed that several of the initially considered phenotypically and functionally distinct Mo subsets represent the same population, only identified by different methods. Furthermore, some Mo subsets exhibit common features with DC or Mac. These common features of Mo subsets as well as their relations to the other cell types are also summarized in Table 1 .

From this one can delineate the following picture of Mo subset composition in peripheral blood. Studies on the size and density of Mo in blood of healthy human donors identified a major subset of large high-density Mo and minor subsets of less dense cells. The major subset was represented by Fc{gamma}R-I (CD64+) Mo [20 21 22 23 24 25 26 27 , 30 , 36 ], which are identical to CD14+/CD16- Mo [38 39 40 , 43 ] and the recently described CD64+/CD16- cells [32, 45]. These cells are classical Mo with typical monocytic phenotype characteristics and functions such as high cytokine production [20 , 33 ], high chemotactic [34 ] and phagocytic activity [30 , 32 ], high cytotoxicity for tumor cells, and suppressive activities in lymphocyte proliferation [26 , 27 ]. In contrast, the different minor subsets of small less dense cells are more heterogeneous than the major typical Mo population, and their phenotypical and functional characterization reveals common features with Mac and myeloid or lymphoid DC.

The minor subset of Fc{gamma}R-I (CD64-) cells exhibits Mo-like high expression of unspecific esterase [30 ], but they also show DC-like high expression of MHC-class-I and -II molecules, high accessory capacity for antigen and alloantigen-induced T cell activation [25 26 27 , 30 , 35 ], and high resistance to killing by CD4+ cytotoxic T cells [36 ], a property that is also described for reticular DC [51 ]. More recent studies described the division of Fc{gamma}R- into a lineage-negative subset of CD64 (Fc{gamma}R-I)-/CD16 (Fc{gamma}R-III)- cells and a further subset of CD64-/CD16+ cells [45 ] (Table 1) and revealed similarities to DC subtypes. The lymphoid morphology and lineage-negative phenotype of CD64-/CD16- cells corresponds to that which is described for lymphoid DC precursors in blood [52 53 54 55 ]. Furthermore, the CD64-/CD16- cells seem to be identical with the recently described lineage-negative CD123 (IL-3R{alpha})+/CD4+/ILT3+/ILT1- plasmacytoid Mo [54 , 56 ], representing blood progenitors for the type 2 DC (DC2) [57 ], which promote Th2 responses [58 ]. They share with CD64-/CD16- cells low accessory and phagocytic activity but high IFN-{alpha}-producing capacity and might be related to the CD4+ lineage-negative blood DC [59 ]. They also have common features with a blood subset that is described as surface marker lineage negative and negative for MPO expression but positive for CD68 [60 ]. These cells proliferate upon IL-3 and do not acquire myeloid features but typical DC characteristics. Furthermore, CD64-/CD16- cells exhibit similarity to the immature lymphoid DC type, which was recently described to be located in the T cell-rich interfollicular region of murine Peyer’s patches [61 ]. In contrast, the subset of CD64-/CD16+ Mo [45 ] might be identical with the CD14dim/CD16+ alveolar Mac-like subset described by Ziegler-Heitbrock because they share the low but consistent expression of myeloid phenotype markers, high expression of CD11c, and high expression of MHC class I and II and costimulatory molecules [30, 39, 40, 45]. In addition, their higher expression of CCR5 and higher chemotactic responsiveness to Mac inflammatory protein 1{alpha} RANTES than CD14+/CD16- typical Mo [44 ] associate CD14dim/CD16- cells to an inflammatory tissue Mac type. CD14dim/CD16+ cells were shown to be highly active in production of IL-12 and induction of IFN-{gamma} release by antigen-stimulated T cells [30, 35, 45], characteristics that are described for Mac but also for Mo-derived mature DC [49 , 62 , 63 ]. Therefore, they could also be related to the recently described DC type I cells promoting Th1 responses [58 ]. Furthermore, recently a CD14+/CD16+ DC precursor with high T cell accessory capacity but also high phagocytic activity was described in human blood [64 ]. These cells share some common features with the novel subset of CD64+/CD16+ Mo [32, 45], which is unique in combining the described myeloid DC characteristics with classical Mo characteristics, as they were described for the typical Fc{gamma}R-I (CD64)+ (= CD14+/CD16-) Mo.


   MO SUBSETS IN PATHOPHYSIOLOGICAL CONDITIONS
TOP
 ABSTRACT
 INTRODUCTION
 MO SUBSETS AS DEFINED...
 MO SUBSETS AS DEFINED...
 MO SUBSETS AND THEIR...
 MO SUBSETS IN PATHOPHYSIOLOGICAL...
DEVELOPMENTAL HISTORY OF MO...
 CONCLUDING REMARKS ON THE...
 REFERENCES
 
In addition to the different Mo subsets identified in peripheral blood of healthy human donors, Mo in different activation or differentiation stages have been described in the local environment of acute and chronic inflammation [65 ]. Thus, Mo that express 27E10 (a heterodimer of MRP8 and MRP15, two Ca2+-binding proteins of the S-100 protein family) were supposed to represent an activated Mo phenotype resulting from interaction of extravasating Mo with the extracellular matrix [66 ] and were present in acute inflammatory processes and absent under chronic inflammatory conditions [67 ].

In contrast, a Mo subset expressing RM3/1 containing more histamine and more histidine decarboxylase (HDC) activity than 27E10+ Mo [68 ] was associated with a down-regulation of inflammatory responses. Furthermore, whereas during acute inflammatory reactions, e.g., in gingivitis, MRP14 was expressed in intravascular Mo and perivascular Mac, in chronic inflammation MRP8 was expressed by Mac in tissue [69 ]. Also, under pathophysiological circumstances changes of Mo subsets in peripheral blood were reported (Table 1) . In line with the high production of cytokines and suppression of HLA-DR expression that is observed in surgical sepsis, one group described a shift to Fc{gamma}R-I+ cells with high production of IL-1ß and IL-6 but low expression of HLA-DR in septic patients, defining high-risk septic patients that might benefit from immunoregulatory therapy [70 ]. In contrast, Fingerle [71 ] described that CD14dim/CD16+/HLA-DR++ Mo, which were shown to be low producers of proinflammatory cytokines in response to LPS [38 ], were expanded in septic patients and at a time when elevated serum levels of IL-6 were observed. An increase of CD16 expression and CD16+ Mo subsets was described in association with different other diseases. Thus, an increase of a CD14dim/CD16+ subset was also observed in blood of HIV+ patients with current opportunistic infections [72 ], AIDS patients [73 ], and in AIDS dementia [74 ]. Correspondingly, in vitro studies demonstrated that HLA-DR and Fc{gamma}R-I were down-regulated in Mo in the presence of HIV-1 envelope glycoprotein 120 (gp120) [75 ] and the proportion of CD14dim/CD16+ Mo increased [73 ]. Furthermore, CD14dim/CD16+ cells exhibiting the typical tissue Mac marker MAX1, p150, and HLA-DR, expressed high intracellular TNF-{alpha} and IL-1ß, and there has been some discussion as to their participation in immune dysfunction during HIV infection [76 ]. Furthermore, these cells express CCR5 [77 ], which is the principal receptor for primary, Mac-tropic viruses [78 ]. Elevated numbers of a Mac-like CD14dim/CD16+ highly phagocytic IL-1-producing subset in pararheumatic systemic vasculitis were also described in recent studies by Scherberich et al. [79 ]. Furthermore, Rothe [80 ] described in patients with an atherogenic lipid profile six different Mo subsets: CD14+/CD16- cells, resembling typical Mo, CD14dim/CD16+ Mo, a CD14+/CD16+ subset (similar to the recently described CD14+/CD16+ subset in blood of healthy donors [Grage-Griebenow et al., unpublished results]), and three CD14dim/CD16- (CD33dim, CD33high, or CD56+) subsets. In contrast, reports of Draude [41 ] suggested that high activity of Fc{gamma}R-I+ (= CD14+/CD16-) Mo in Sc receptor-mediated binding of LDL might be important for foam cell formation in atherosclerosis, indicating that the role of these different Mo subsets in this disease is still debatable. The recent findings that allergic children show lower virus-induced IFN-{alpha} production compared to non-allergic children [A. Bufe and M. Ernst, Research Center Borstel, unpublished observation] suggest possible changes in the number or activity of the high IFN-{alpha}-producing plasmacytoid CD64-/CD16- [45, 56], Th2-promoting [58 ] cells in allergy. Besides this association of diseases with CD16 expression, changes in MHC class II and CD4 expression were also described in association with HIV infection [81 ], in psoriatic, and in atopic dermatitis patients [82 ]. Finally, it should be mentioned that changes in phenotype and function of Mo subsets in peripheral blood Mo are not only influenced by the physiological and pathophysiological conditions, but also by the treatment of patients with cytokines. Thus, in melanoma patients M-CSF treatment increased the general size and number of Mo in peripheral blood and the relative percentage of CD14dim/CD16+ Mo [83 ]. In addition, the CD14 expression on CD14+/CD16- typical Mo was also enhanced. In contrast, GM-CSF increased the cell size and relative percentage of CD14dim Mo, but decreased the proportion of CD16+ Mo therein. In addition, it decreased the CD14 antigen density on CD14+/CD16- Mo. This phenomenon was accompanied by functional changes, as Mo from M-CSF-treated patients exhibited ADCC and increased cytotoxicity toward melanoma cells compared to monocytes from GM-CSF-treated patients. A report by Weiner [84 ] demonstrated that an increase of CD16+ Mo was only observed after treatment with M-CSF in combination with IFN-{gamma}, but not when used alone, and the changes in the Mo subsets appeared to be a result of proliferation and differentiation of blood Mo. In conclusion, these data indicate that the composition of Mo subsets, as well as the activation and differentiation state, is influenced by the actual pathophysiological circumstances in disease. The high number of reports dealing with this subject, and the sometimes controversial results also indicate that the individual role of these subsets in diseases is still under and requires further investigation.


   DEVELOPMENTAL HISTORY OF MO SUBSETS
TOP
 ABSTRACT
 INTRODUCTION
 MO SUBSETS AS DEFINED...
 MO SUBSETS AS DEFINED...
 MO SUBSETS AND THEIR...
 MO SUBSETS IN PATHOPHYSIOLOGICAL...
 DEVELOPMENTAL HISTORY OF MO...
CONCLUDING REMARKS ON THE...
 REFERENCES
 
The described heterogeneity within blood Mo and related tissue cell types raises the question of the developmental origin of the subsets, and whether these represent precursor or fully differentiated cell types. These questions remain under discussion, but the functional and phenotypical analyses, as described above, supply some answers. It is well known that CD14+ Mo (mainly resembling CD64+/CD16- cells) as they appear in blood can give rise to immature or mature myeloid DC as well as to Mac, dependent on the cytokine environment [49 , 62 , 63 ]. In these in vitro differentiation studies it has been shown that GM-CSF and IL-4 generate an immature DC type that is still able to phagocytose and take up antigens. Further cytokines and chemokines, stimulation with LPS, and phagocytosis are involved in the regulation of mobility and function of blood immature DC progenitors and in further maturation to fully differentiated myeloid DC with Th1 stimulation activity [85 , 86 ]. Having seen that CD14+ blood progenitors are able to generate DC, CD14+ cells are also capable of maturing into tissue Mac, which is shown in in vitro differentiation studies [40 , 87 ], demonstrating that in the presence of human serum CD14+ Mo develop into alveolar-like Mac with high expression of HLA-DR and CD16. Furthermore, in vivo the number of CD16+ Mo in peripheral blood could be expanded by administration of M-CSF in the primates and humans [88 ]. But a portion of these cells show characteristics of large granular lymphocytes, indicating that both cell types share a common myeloid development pathway. On this background one can imagine different developmental pathways for the described minor DC-like cell types in peripheral blood. Both CD16+ subsets (CD64+ and CD64- = CD16+/CD14dim) exhibit with their high stimulatory capacity for Th1 responses and high expression of HLA-DR, CD86, CD11c characteristics of fully differentiated mature DC type 1 [1 , 49 , 89 ]. Because they express myeloid surface markers and Mo morphology, they might represent myeloid DC and possibly develop from the CD14+/CD16- blood Mo or from a common CD14+ precursor that generates both, CD14+/CD16- typical Mo and both CD16+ (CD64+/CD14+ and CD64-/CD14dim) cell subsets. The latter would therefore belong to the so-called CD14-dependent DC, which were discriminated from the CD14-independent pathway generating Langerhans cells [1 , 89 ]. Because CD64+/CD16+ cells exhibit higher expression of HLA-DR and CD11c, and higher T cell stimulatory activity than CD64-/CD16+ cells, they could represent an even later maturation step in the same DC development pathway. But this would be in contrast to the observation that CD14 gets lost during this maturation [1 , 89 ]. Although both CD16+ subsets exhibit accessory activities of mature DC, they lack some typical phenotypical markers of mature DC, such as CD83 and CD1 [89 ]. Because both CD16+ subsets also show characteristics of Mac, such as high expression of HLA-DR, CD68, and CD16 [40 , 44 , 87 , 90 ], and even share the high CD16 expression with large granular lymphocytes (LGL) [88 ], they could also represent precursors or differentiated stages in Mac or LGL development. Furthermore, the finding that CD64+/CD16+ cells combine classical Mo and DC features on the same cells raises the possibility that they represent a maturation stage one step upstream of CD64+/CD16- Mo, which still enables differentiation into both types, Mac and DC. Finally, one cannot exclude that both CD16+ subsets result from separate lines in the development of DC, Mac, or LGL from a common CD14+ precursor. In contrast to the CD16+ cell types, the plasmacytoid morphology and lineage-negativity of the high IFN-{alpha}-producing CD123+/CD4+ cells indicate the generation from a separate lymphoid precursor. This was confirmed by the finding that T cells and lineage-negative DC share a common CD11b-/CD13-/CD33-/CD14-/CD11c-/CD4+ lymphoid precursor in peripheral blood [53 , 57 ]. When culturing these cells in the presence of IL-3 and CD40 ligand, they develop into fully differentiated DC type 2 [57 ]. Taken together, none of the Mo and DC subsets appearing in blood seems to represent a fully irreversible mature cell type. All might still have the capacity to undergo further differentiation. This might also be confirmed by the reports showing that different Mo subsets could be increased or decreased under pathophysiological circumstances (see above) dependent on the local environment.


   CONCLUDING REMARKS ON THE IMMUNOREGULATORY ROLE OF MO SUBSETS
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 ABSTRACT
 INTRODUCTION
 MO SUBSETS AS DEFINED...
 MO SUBSETS AS DEFINED...
 MO SUBSETS AND THEIR...
 MO SUBSETS IN PATHOPHYSIOLOGICAL...
 DEVELOPMENTAL HISTORY OF MO...
 CONCLUDING REMARKS ON THE...
REFERENCES
 
The phenotypical and functional dissociation between blood Mo subsets, as they were summarized here, also indicates differences in their immunoregulatory roles: the major subset of typical large, high-density Fc{gamma}R-I (CD64)+ Mo represents potent phagocytes that are active in the innate immune response against pathogens and are finally responsible for the down-regulation of an established immune response. Their high expression of chemotactic ligand receptors [34 ] indicates high susceptibility to chemotactic agents and chemokines and enables their early recruitment to the site of inflammation where they produce high amounts of proinflammatory cytokines [91 ] leading to recruitment and activation of other Mo and other effector cells, and therefore, promote an early inflammatory response. Therefore, Fc{gamma}R-I+ Mo are also considered an indicator for poor prognosis, being increased in patients with septic shock and rendering them anergic toward opportunistic infections [33 ]. At the same time, the production of reactive oxygen intermediates [32 ] enables the direct microbicidal activity of these cells, and to the successful removal of pathogens or dead cells by phagocytosis, leading finally to a down-regulation of the inflammatory responses. These cells are potent producers of PGE2 [21 ] and thus may mediate suppressive antigen [25 26 27 , 92 ] or alloantigen [93 ] -induced lymphoproliferation, and may contribute to a down-regulation of an adaptive immune response. On the contrary, the minor subset of CD14dim/CD16+ (= CD64-/CD16+) Mo subsets are low in phagocytic activity and cytokine production but exhibit high expression of MHC class I and II [38 , 39 ] and costimulatory B7 molecules, and are effective in the induction of adaptive Th1 responses against bacterial and viral infections [30, 35, 36, 45]. Furthermore, the relative resistance of Fc{gamma}R-I (CD64-) Mo to T cell killing [36 ] even provides the possibility of prolonged T cell inflammatory responses. Because the novel population of CD64+/CD16+ Mo exhibits typical characteristics of both, Mo and DC, it might be efficiently active in innate as well as adaptive immune responses. Along these lines, an increase in CD16+ Mo subsets is associated with different acute inflammatory disease and infections. Finally, because IFN-{alpha} production is an early mechanism in innate defense against viruses [94 ] and tumors [95 ], and has immunomodulatory effects by increasing MHC class I [96 ], Fc{gamma}R-I [97 ] expression, and IL-2 release by activated T cells [98 ], the high IFN-{alpha}-producing CD64-/CD16-, lineage-negative, plasmacytoid cells [56 ] might represent the main population responsible for direct antiviral resistance, but might also be able to modulate adaptive responses. Because these cells also resemble progenitors of DC2 [58 ], they could be important in the regulation of Th2 responses in allergy and adaptive defense against parasites.

In conclusion, this diversity within blood Mo might reflect their different states of activation and/or differentiation, enabling them to induce rapid innate and long-lasting adaptive immune responses.

Received April 12, 2000; revised August 7, 2000; accepted September 21, 2000.


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  1. Santiago-Schwarz, F. (1999) Positive and negative regulation of the myeloid dendritic cell lineage J. Leukoc. Biol. 66,209-216[Abstract]
  2. Rappold, I., Ziegler, B. L., Kohler, I., Marchetto, S., Rosnet, O., Birnbaum, D., Simmons, P. J., Zannettino, A. C., Hill, B., Neu, S., Knapp, W., Alitalo, R., Alitalo, K., Ullrich, A., Kanz, L., Buhring, H. J. (1997) Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase Blood 90,111-125[Abstract/Free Full Text]
  3. Bender, J. G., Unverzagt, K. L., Walker, D. E., Lee, W., Van Epps, D. E., Smith, D. H., Stewart, C. C., To, L. B. (1991) Identification and comparison of CD34-positive cells and their subpopulations from normal peripheral blood and bone marrow using multicolor flow cytometry Blood 77,2591-2596[Abstract/Free Full Text]
  4. Mattern, T., Girroleit, G., Flad, H. D., Rietschel, E. T., Ulmer, A. J. (1999) CD34(+) hematopoietic stem cells exert accessory function in lipopolysaccharide-induced T cell stimulation and CD80 expression on monocytes J. Exp. Med. 189,693-700[Abstract/Free Full Text]
  5. Qiao, L., Braunstein, J., Golling, M., Schurmann, G., Autschbach, F., Moller, P., Meuer, S. (1996) Differential regulation of human T cell responsiveness by mucosal versus blood monocytes Eur. J. Immunol. 26,922-927[Medline]
  6. Wintergerst, E. S., Jelk, J., Asmis, R. (1998) Differential expression of CD14, CD36 and the LDL receptor on human monocyte-derived macrophages. A novel cell culture system to study macrophage differentiation and heterogeneity. Histochem. Cell Biol. 110,231-241[Medline]
  7. Takahashi, K., Naito, M., Takeya, M. (1996) Development and heterogeneity of macrophages and their related cells through their differentiation pathways Pathol. Int. 46,473-485[Medline]
  8. Akiyama, Y., Miller, P. J., Thurman, G. B., Neubauer, R. H., Oliver, C., Favilla, T., Beman, J. A., Oldham, R. K., Stevenson, H. C. (1983) Characterization of a human blood monocyte subset with low peroxidase activity J. Clin. Invest. 72,1093-1105
  9. Akiyama, Y., Stevenson, G. W., Schlick, E., Matsushima, K., Miller, P. J., Stevenson, H. C. (1985) Differential ability of human blood monocyte subsets to release various cytokines J. Leukoc. Biol. 37,519-530[Abstract]
  10. Yasaka, T., Mantich, N. M., Boxer, L. A., Baehner, R. L. (1981) Functions of human monocyte and lymphocyte subsets obtained by countercurrent centrifugal elutriation: differing functional capacities of human monocyte subsets J. Immunol. 127,1515-1518[Abstract]
  11. Weiner, R. S., Mason, R. R. (1984) Subfractionation of human blood monocyte subsets with Percoll Exp. Hematol. 12,800-804[Medline]
  12. Figdor, C. G., Bont, W. S., Touw, I., de Roos, J., Roosnek, E. E., de Vries, J. E. (1982) Isolation of functionally different human monocytes by counterflow centrifugation elutriation Blood 60,46-53[Abstract/Free Full Text]
  13. Elias, J. A., Chien, P., Gustilo, K. M., Schreiber, A. D. (1985) Differential interleukin-1 elaboration by density-defined human monocyte subpopulations Blood 66,298-301[Abstract/Free Full Text]
  14. Fernandez, R. C., Lee, S. H., Fernandez, L. A., Pope, B. L., Rozee, K. R. (1986) Production of interferon by peripheral blood mononuclear cells from normal individuals and patients with chronic lymphocytic leukemia J. Interferon Res. 6,573-580[Medline]
  15. Chehimi, J., Starr, S. E., Kawashima, H., Miller, D. S., Trinchieri, G., Perussia, B., Bandyopadhyay, S. (1989) Dendritic cells and IFN-alpha-producing cells are two functionally distinct non-B, non-monocytic HLA-DR+ cell subsets in human peripheral blood Immunology 68,488-490
  16. Schreiber, A. D., Kelley, M., Dziarski, A., Levinson, A. I. (1983) Human monocyte functional heterogeneity: monocyte fractionation by discontinuous albumin gradient centrifugation Immunology 49,231-238[Medline]
  17. Arenson, E. B., Epstein, M. B., Seeger, R. C. (1979) Monocyte subsets in neonates and children Pediatrics 64,740-744[Abstract]
  18. Esa, A. H., Noga, S. J., Donnenberg, A. D., Hess, A. D. (1986) Immunological heterogeneity of human monocyte subsets prepared by counterflow centrifugation elutriation Immunology 59,95-99[Medline]
  19. Connor, R. I., Shen, L., Fanger, M. W. (1990) Evaluation of the antibody-dependent cytotoxic capabilities of individual human monocytes. Role of Fc gamma RI and Fc gamma RII and the effects of cytokines at the single cell level J. Immunol. 145,1483-1489[Abstract]
  20. Szabo, G., Miller-Graziano, C. L., Wu, J. Y., Takayama, T., Kodys, K. (1990) Differential tumor necrosis factor production by human monocyte subsets J. Leukoc. Biol. 47,206-216[Abstract]
  21. Szabo, G., Miller, C. L., Kodys, K. (1990) Antigen presentation by the CD4 positive monocyte subset J. Leukoc. Biol. 47,111-120[Abstract]
  22. Pryjma, J., Pituch-Noworolska, A., Ruggiero, I., Zembala, M. (1985) The regulation of polyclonal immunoglobulin synthesis by FcR+ and FcR- monocyte subsets Clin. Immunol. Immunopathol. 37,245-252[Medline]
  23. Pryjma, J., Flad, H. D., Gruber, M., Ernst, M. (1986) Monocyte-T-cell interactions in the regulation of polyclonal B-cell response Scand. J. Immunol. 24,21-28[Medline]
  24. Pryjma, J., Mytar, B., Loppnow, H., Ernst, M., Zembala, M., Flad, H. D. (1992) FcR+ and FcR- monocytes differentially secrete monokines during pokeweed mitogen-induced T-cell-monocyte interactions Immunology 75,355-360[Medline]
  25. Pryjma, J., Kowalczyk, D., Ruggiero, I., Zembala, M. (1992) Immunoregulation of lymphoproliferation in vitro by monocytes and their subpopulations. II. Phenotypic changes of T cells in cultures activated with antigen and mitogen Arch. Immunol. Ther. Exp. (Warsz.) 40,139-143[Medline]
  26. Zembala, M., Uracz, W., Ruggiero, I., Mytar, B., Pryjma, J. (1984) Isolation and functional characteristics of FcR+ and FcR- human monocyte subsets J. Immunol. 133,1293-1299[Abstract]
  27. Zembala, M., Pryjma, J., Uracz, W., Kowalczyk, D., Ruggiero, I., Mytar, B. (1986) Regulation of human lymphocyte response in vitro by monocytes and their subsets Folia Biol. (Praha) 32,1-11[Medline]
  28. Fanger, N. A., Wardwell, K., Shen, L., Tedder, T. F., Guyre, P. M. (1996) Type I (CD64) and type II (CD32) Fc gamma receptor-mediated phagocytosis by human blood dendritic cells J. Immunol. 157,541-548[Abstract]
  29. Tuijnman, W. B., van de Winkel, J. G., Capel, P. J. (1990) A flow cytometric rosetting assay for the analysis of IgG-Fc receptor interactions J. Immunol. Meth. 127,207-214[Medline]
  30. Grage-Griebenow, E., Lorenzen, D., Fetting, R., Flad, H. D., Ernst, M. (1993) Phenotypical and functional characterization of Fc gamma receptor I (CD64)-negative monocytes, a minor human monocyte subpopulation with high accessory and antiviral activity Eur. J. Immunol. 23,3126-3135[Medline]
  31. Shen, H. H., Talle, M. A., Goldstein, G., Chess, L. (1983) Functional subsets of human monocytes defined by monoclonal antibodies: a distinct subset of monocytes contains the cells capable of inducing the autologous mixed lymphocyte culture J. Immunol. 130,698-705[Abstract]
  32. Grage-Griebenow, E., Flad, H. D., Ernst, M., Bzowska, M., Skrzeczynska, J., Pryjma, J. (2000) Human Mo subset as defined by expression of CD64 and CD16 differ in phagocytic activity and generation of oxygen intermediates Immunobiology 202,42-50[Medline]
  33. Schinkel, C., Sendtner, R., Zimmer, S., Faist, E. (1998) Functional analysis of monocyte subsets in surgical sepsis J. Trauma 44,743-748[Medline]
  34. Ohura, K., Katona, I. M., Wahl, L. M., Chenoweth, D. E., Wahl, S. M. (1987) Co-expression of chemotactic ligand receptors on human peripheral blood monocytes J. Immunol. 138,2633-2639[Abstract]
  35. Grage-Griebenow, E., Flad, H. D., Ernst, M. (1996) Fc gamma receptor I (CD64)-negative human monocytes are potent accessory cells in viral antigen-induced T cell activation and exhibit high IFN-alpha-producing capacity J. Leukoc. Biol. 60,389-396[Abstract]
  36. Grage-Griebenow, E., Baran, J., Loppnow, H., Los, M., Ernst, M., Flad, H. D., Pryjma, J. (1997) An Fc gamma receptor I (CD64)-negative subpopulation of human peripheral blood monocytes is resistant to killing by antigen-activated CD4-positive cytotoxic T cells Eur. J. Immunol. 27,2358-2365[Medline]
  37. Lombardi, G., Piccolella, E., Vismara, D., Colizzi, V., Zembala, M. (1985) Monocyte subsets in the production of inhibitory factor by Candida albicans-activated human T cells Immunology 56,373-376[Medline]
  38. Ziegler-Heitbrock, H. W., Strobel, M., Kieper, D., Fingerle, G., Schlunck, T., Petersmann, I., Ellwart, J., Blumenstein, M., Haas, J. G. (1992) Differential expression of cytokines in human blood monocyte subpopulations [see comments] Blood 79,503-511[Abstract/Free Full Text]
  39. Ziegler-Heitbrock, H. W., Strobel, M., Fingerle, G., Schlunck, T., Pforte, A., Blumenstein, M., Haas, J. G. (1991) Small (CD14+/CD16+) monocytes and regular monocytes in human blood Pathobiology 59,127-130[Medline]
  40. Ziegler-Heitbrock, H. W., Fingerle, G., Strobel, M., Schraut, W., Stelter, F., Schutt, C., Passlick, B., Pforte, A. (1993) The novel subset of CD14+/CD16+ blood monocytes exhibits features of tissue macrophages Eur. J. Immunol. 23,2053-2058[Medline]
  41. Draude, G., von Hundelshausen, P., Frankenberger, M., Ziegler-Heitbrock, H. W., Weber, C. (1999) Distinct scavenger receptor expression and function in the human CD14(+)/CD16(+) monocyte subset Am. J. Physiol. 276,H1144-H1149[Abstract/Free Full Text]
  42. Allan, D. S., Colonna, M., Lanier, L. L., Churakova, T. D., Abrams, J. S., Ellis, S. A., McMichael, A. J., Braud, V. M. (1999) Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells J. Exp. Med. 189,1149-1156[Abstract/Free Full Text]
  43. Thomas, R., Lipsky, P. E. (1994) Human peripheral blood dendritic cell subsets Isolation and characterization of precursor and mature antigen-presenting cells. J. Immunol. 153,4016-4028
  44. Weber, C., Belge, K. U., von Hundelshausen, P., Draude, G., Steppich, B., Mack, M., Frankenberger, M., Weber, K. S., Ziegler-Heitbrock, H. W. (2000) Differential chemokine receptor expression and function in human monocyte subpopulations J. Leukoc. Biol. 67,699-704[Abstract]
  45. Grage-Griebenow, E., Zawatzky, R., Kahlert, H., Brade, L., Flad, H. D., Ernst, M. (2000) Identification of a novel DC-like subset of CD64-KD16+ blood mo Eur. J. Immunol. In press
  46. Sandberg, K., Eloranta, M. L., Johannisson, A., Alm, G. V. (1991) Flow cytometric analysis of natural interferon-alpha producing cells Scand. J. Immunol. 34,565-576[Medline]
  47. Feldman, S. B., Ferraro, M., Zheng, H. M., Patel, N., Gould-Fogerite, S., Fitzgerald-Bocarsly, P. (1994) Viral induction of low frequency interferon-alpha producing cells Virology 204,1-7[published errata appear in Virology (1995) 206, 1159 and (1995) 207, 342][Medline]
  48. Svennson, H., Johannisson, A., Nikkilä, T., Alm, G. V., Cedermark, B. (2000) The cell surface phenotype of human natural interferon-alpha-producing cells as determined by flow cytometry Scand. J. Immunol. 44,164-172
  49. Banchereau, J., Steinman, R. M. (1998) Dendritic cells and the control of immunity Nature 392,245-252[Medline]
  50. Nunez, G., Ball, E. J., Stastny, P. (1987) Antigen presentation by adherent cells from human peripheral blood. Correlation between T-cell activation and expression of HLA-DQ and -DR antigens Hum. Immunol. 19,29-39[Medline]
  51. Hahn, S., Gehri, R., Erb, P. (1995) Mechanism and biological significance of CD4-mediated cytotoxicity Immunol. Rev. 146,57-79[Medline]
  52. Macey, M. G., McCarthy, D. A., Vogiatzi, D., Brown, K. A., Newland, A. C. (1998) Rapid flow cytometric identification of putative CD14- and CD64- dendritic cells in whole blood Cytometry 31,199-207[Medline]
  53. Bruno, L., Res, P., Dessing, M., Cella, M., Spits, H. (1997) Identification of a committed T cell precursor population in adult human peripheral blood J. Exp. Med. 185,875-884[Abstract/Free Full Text]
  54. Strobl, H., Scheinecker, C., Riedl, E., Csmarits, B., Bello-Fernandez, C., Pickl, W. F., Majdic, O., Knapp, W. (1998) Identification of CD68+lin- peripheral blood cells with dendritic precursor characteristics J. Immunol. 161,740-748[Abstract/Free Full Text]
  55. Blom, J., Nielsen, C., Rhodes, J. M. (1993) An ultrastructural study of HIV-infected human dendritic cells and monocytes/macrophages APMIS 101,672-680[Medline]
  56. Cella, M., Jarrossay, D., Facchetti, F., Alebardi, O., Nakajima, H., Lanzavecchia, A., Colonna, M. (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon [see comments] Nat. Med. 5,919-923[Medline]
  57. Grouard, G., Rissoan, M. C., Filgueira, L., Durand, I., Banchereau, J., Liu, Y. J. (1997) The enigmatic plasmacytoid T-cells develop into dendritic cells with (IL)-3 and CD40-ligand J. Exp. Med. 185,1101-1111[Abstract/Free Full Text]
  58. Rissoan, M. C., Soumelis, V., Kadowaki, N., Grouard, G., Briere, F., de Waal, M. R., Liu, Y. J. (1999) Reciprocal control of T helper cell and dendritic cell differentiation [see comments] Science 283,1183-1186[Abstract/Free Full Text]
  59. Ferbas, J. J., Toso, J. F., Logar, A. J., Navratil, J. S., Rinaldo, C. R., Jr. (1994) CD4+ blood dendritic cells are potent producers of IFN-alpha in response to in vitro HIV-1 infection J. Immunol. 152,4649-4662[Published erratum appears in J. Immunol. (1994) 153, 910][Abstract]
  60. Strobl, H., Scheinecker, C., Riedl, E., Csmarits, B., Bello-Fernandez, C., Pickl, W. F., Majdic, O., Knapp, W. (1998) Identification of CD68+lin- peripheral blood cells with dendritic precursor characteristics J. Immunol. 161,740-748
  61. Iwasaki, A., Kelsall, B. L. (2000) Localization of distinct Peyer’s patch dendritic cell subsets and their recruitment by chemokines macrophage inflammatory protein (MIP)-3alpha, MIP-3beta, and secondary lymphoid organ chemokine J. Exp. Med. 191,1381-1394[Abstract/Free Full Text]
  62. Sallusto, F., Lanzavecchia, A. (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha J. Exp. Med. 179,1109-1118[Abstract/Free Full Text]
  63. Gieseler, R., Heise, D., Soruri, A., Schwartz, P., Peters, J. H. (1998) In-vitro differentiation of mature dendritic cells from human blood monocytes Dev. Immunol. 6,25-39[Medline]
  64. Schakel, K., Mayer, E., Federle, C., Schmitz, M., Riethmuller, G., Rieber, E. P. (1998) A novel dendritic cell population in human blood: one-step immunomagnetic isolation by a specific mAb (M-DC8) and in vitro priming of cytotoxic T lymphocytes Eur. J. Immunol. 28,4084-4093[Medline]
  65. Hauptmann, S., Bernauer, J., Zwadlo-Klarwasser, G., Klosterhalfen, B., Kirkpatrick, C. J. (1994) Differential adherence of the human monocyte subsets 27E10 and RM3/1 to cytokine- or glucocorticoid-treated endothelial cells Pathobiology 62,262-268[Medline]
  66. Mahnke, K., Bhardwaj, R., Sorg, C. (19956) Heterodimers of the calcium-binding proteins MRP8 and MRP14 are expressed on the surface of human monocytes upon adherence to fibronectin and collagen. Relation to TNF-alpha, IL-6, and superoxide production J. Leukoc. Biol. 57,63-71[Abstract]
  67. Peters, K. M., Koberg, K., Rosendahl, T., Klosterhalfen, B., Straub, A., Zwadlo-Klarwasser, G. (1996) Macrophage reactions in septic arthritis Arch. Orthop. Trauma Surg. 115,347-350
  68. Zwadlo-Klarwasser, G., Vogts, M., Hamann, W., Belke, K., Baron, J., Schmutzler, W. (1998) Generation and subcellular distribution of histamine in human blood monocytes and monocyte subsets Inflamm. Res. 47,434-439[Medline]
  69. Zwadlo, G., Bruggen, J., Gerhards, G., Schlegel, R., Sorg, C. (1988) Two calcium-binding proteins associated with specific stages of myeloid cell differentiation are expressed by subsets of macrophages in inflammatory tissues Clin. Exp. Immunol. 72,510-515[Medline]
  70. Schinkel, C., Sendtner, R., Zimmer, S., Walz, A., Hultner, L., Faist, E. (1999) Evaluation of Fc-receptor positive (FcR+) and negative (FcR-) monocyte subsets in sepsis Shock 11,229-234[Medline]
  71. Fingerle, G., Pforte, A., Passlick, B., Blumenstein, M., Strobel, M., Ziegler-Heitbrock, H. W. (1993) The novel subset of CD14+/CD16+ blood monocytes is expanded in sepsis patients Blood 82,3170-3176[Abstract/Free Full Text]
  72. Dunne, J., Feighery, C., Whelan, A. (1996) Beta-2-microglobulin, neopterin and monocyte Fc gamma receptors in opportunistic infections of HIV-positive patients Br. J. Biomed. Sci. 53,263-269[Medline]
  73. Zembala, M., Bach, S., Szczepanek, A., Mancino, G., Colizzi, V. (1997) Phenotypic changes of monocytes induced by HIV-1 gp120 molecule and its fragments Immunobiology 197,110-121[Medline]
  74. Pulliam, L., Gascon, R., Stubblebine, M., McGuire, D., McGrath, M. S. (1997) Unique monocyte subset in patients with AIDS dementia Lancet 349,692-695[Medline]
  75. Dürrbaum-Landmann, I., Kaltenhäuser, E., Flad, H. D., Ernst, M. (1994) HIV-1 envelope protein gp120 affects phenotype and function of monocytes in vitro J. Leukoc. Biol. 55,545-551[Abstract]
  76. Thieblemont, N., Weiss, L., Sadeghi, H. M., Estcourt, C., Haeffner-Cavaillon, N. (1995) CD14lowCD16high: a cytokine-producing monocyte subset which expands during human immunodeficiency virus infection Eur. J. Immunol. 25,3418-3424[Medline]
  77. Weber, C., Belge, K. U., von Hundelshausen, P., Draude, G., Steppich, B., Mack, M., Frankenberger, M., Weber, K. S., Ziegler-Heitbrock, H. W. (2000) Differential chemokine receptor expression and function in human monocyte subpopulations J. Leukoc. Biol. 67,699-704
  78. Wu, L., Paxton, W. A., Kassam, N., Ruffing, N., Rottman, J. B., Sullivan, N., Choe, H., Sodroski, J., Newman, W., Koup, R. A., Mackay, C. R. (1997) CCR5 levels and expression pattern correlate with infectability by macrophage-tropic HIV-1, in vitro J. Exp. Med. 185,1681-1691[Abstract/Free Full Text]
  79. Scherberich, J. E., Nockher, W. A. (1999) CD14++ monocytes, CD14+/CD16+ subset and soluble CD14 as biological markers of inflammatory systemic diseases and monitoring immunosuppressive therapy Clin. Chem. Lab. Med. 37,209-213[Medline]
  80. Rothe, G., Gabriel, H., Kovacs, E., Klucken, J., Stohr, J., Kindermann, W., Schmitz, G. (1996) Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia Arterioscler. Thromb. Vasc. Biol. 16,1437-1447[Abstract/Free Full Text]
  81. Schnizlein-Bick, C. T., Sherman, M. R., Boggs, D. L., Leemhuis, T. B., Fife, K. H. (1992) Incidence of HIV infection in monocyte subpopulations characterized by CD4 and HLA-DR surface density AIDS 6,151-156[Medline]
  82. Zheng, M., Mrowietz, U. (1997) Phenotypic differences between human blood monocyte subpopulations in psoriasis and atopic dermatitis J. Dermatol. 24,370-378[Medline]
  83. Schmid, I., Baldwin, G. C., Jacobs, E. L., Isacescu, V., Neagos, N., Giorgi, J. V., Glaspy, J. A. (1995) Alterations in phenotype and cell-surface antigen expression levels of human monocytes: differential response to in vivo administration of rhM-CSF or rhGM-CSF Cytometry 22,103-110[Medline]
  84. Weiner, L. M., Li, W., Holmes, M., Catalano, R. B., Dovnarsky, M., Padavic, K., Alpaugh, R. K. (1994) Phase I trial of recombinant macrophage colony-stimulating factor and recombinant gamma-interferon: toxicity, monocytosis, and clinical effects Cancer Res 54,4084-4090[Abstract/Free Full Text]
  85. Ferrero, E., Vettoretto, K., Bondanza, A., Villa, A., Resnati, M., Poggi, A., Zocchi, M. R. (2000) uPA/uPAR system is active in immature dendritic cells derived from CD14+CD34+ precursors and is down-regulated upon maturation J. Immunol. 164,712-718[Abstract/Free Full Text]
  86. Jaksits, S., Kriehuber, E., Charbonnier, A. S., Rappersberger, K., Stingl, G., Maurer, D. (1999) CD34+ cell-derived CD14+ precursor cells develop into Langerhans cells in a TGF-beta 1-dependent manner J. Immunol. 163,4869-4877[Abstract/Free Full Text]
  87. Andreesen, R., Brugger, W., Scheibenbogen, C., Kreutz, M., Leser, H. G., Rehm, A., Lohr, G. W. (1990) Surface phenotype analysis of human monocyte to macrophage maturation J. Leukoc. Biol. 47,490-497[Abstract]
  88. Munn, D. H., Bree, A. G., Beall, A. C., Kaviani, M. D., Sabio, H., Schaub, R. G., Alpaugh, R. K., Weiner, L. M., Goldman, S. J. (1996) Recombinant human macrophage colony-stimulating factor in nonhuman primates: selective expansion of a CD16+ monocyte subset with phenotypic similarity to primate natural killer cells Blood 88,1215-1224[Published erratum appears in Blood (1996) 88, 4083][Abstract/Free Full Text]
  89. Caux, C., Massacrier, C., Vanbervliet, B., Dubois, B., Durand, I., Cella, M., Lanzavecchia, A., Banchereau, J. (1997) CD34+ hematopoietic progenitors from human cord blood differentiate along two independent dendritic cell pathways in response to granulocyte-macrophage colony-stimulating factor plus tumor necrosis factor alpha: II Functional analysis. Blood 90,1458-1470
  90. Levy, P. C., Utell, M. J., Fleit, H. B., Roberts, N. J., Jr, Ryan, D. H., Looney, R. J. (1991) Characterization of human alveolar macrophage Fc gamma receptor III: a transmembrane glycoprotein that is shed under in vitro culture conditions Am. J. Respir. Cell Mol. Biol. 5,307-314
  91. Frankenberger, M., Sternsdorf, T., Pechumer, H., Pforte, A., Ziegler-Heitbrock, H. W. (1996) Differential cytokine expression in human blood monocyte subpopulations: a polymerase chain reaction analysis Blood 87,373-377[Abstract/Free Full Text]
  92. Misra, N., Selvakumar, M., Singh, S., Bharadwaj, M., Ramesh, V., Misra, R. S., Nath, I. (1995) Monocyte derived IL 10 and PGE2 are associated with the absence of Th 1 cells and in vitro T cell suppression in lepromatous leprosy Immunol. Lett. 48,123-128[Medline]
  93. Mielcarek, M., Martin, P. J., Torok-Storb, B. (1997) Suppression of alloantigen-induced T-cell proliferation by CD14+ cells derived from granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells [see comments] Blood 89,1629-1634[Abstract/Free Full Text]
  94. Ronni, T., Sareneva, T., Pirhonen, J., Julkunen, I. (1995) Activation of IFN-alpha, IFN-gamma, MxA, and IFN regulatory factor 1 genes in influenza A virus-infected human peripheral blood mononuclear cells J. Immunol. 154,2764-2774[Abstract]
  95. Peest, D. (1999) The role of alpha-interferon in multiple myeloma Pathol. Biol. (Paris) 47,172-177[Medline]
  96. Garotta, G., Talmadge, K. W., Pink, J. R., Dewald, B., Baggiolini, M. (1986) Functional antagonism between type I and type II interferons on human macrophages Biochem. Biophys. Res. Commun. 140,948-954[Medline]
  97. Fultz, M. J., Vogel, S. N. (1992) Interferon alpha-induced changes in Fc gamma R-specific mRNA expression and isotype-specific, Fc gamma R-mediated phagocytosis in C3H/OuJ (Lpsn) and C3H/HeJ (Lpsd) macrophages J. Leukoc. Biol. 51,300-304[Abstract]
  98. Holan, V., Kohno, K., Minowada, J. (1991) Natural human interferon-alpha augments interleukin-2 production by a direct action on the activated IL-2-producing T cells J. Interferon Res. 11,319-325[Medline]

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