(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
and
M. Ernst
* Experimental Pneumology, Ruhr-University Bochum
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
|
|---|
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
|
|---|
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
-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
|
|---|
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-
(IFN-
). 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-
-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
-receptor (Fc
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
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
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-
-producing capacity and exhibiting potent APC capacity.
 |
MO SUBSETS AS DEFINED BY THEIR SURFACE ANTIGEN CHARACTERISTICS
|
|---|
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
R alone or in
combination with other surface markers and functions. Mo expressing
Fc
R-I and -II, but not Mo expressing Fc
R-III, were reported to
efficiently mediate ADCC [19
]. Early isolation
procedures for the separation of Fc
R+ and
Fc
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
R of Mo is mainly mediated by Fc
R-I
[28
], Fc
R-II and -III can also engage in rosette
formation [29
]. Therefore, in later studies
immunofluorescence labeling with Fc
R-specific Ab and flow cytometric
cell sorting for the exact definition and separation of Mo subsets were
employed [19
, 28
, 30
,
31
]. Fc
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
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
(TNF-
) [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
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
R-I- Mo appeared to be small monocytes, exhibiting
high IFN-
-producing capacity [30
, 35
]
and high accessory capacity for antigen (PPD and influenza A
antigen)-driven T cell activation compared to regular or
Fc
R-I+ Mo [25
26
27
, 30
,
35
, 36
]. In addition, Fc
R-
Mo were found to be better producers of plasminogen activator
correlating with higher APC function for TT [20
].
Fc
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
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
R-I- Mo and not with Fc
R+ or regular
Mo as described before [8
, 9
,
12
]. Recently, Fc
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
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
R expression but are not
identical.
In contrast to Fc
R-I (CD64), Fc
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
R-III. Studies of Ziegler-Heitbrock et al.
[38
, 39
] revealed different functions
between Mo expressing or lacking Fc
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
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
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
/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
R-I+ and
Fc
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
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-
release in response to viruses
(NDV, Sendai, influenza type A antigens), a function they have in
common with the natural IFN-
-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
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
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
|
|---|
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
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
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
R- into a lineage-negative
subset of CD64 (Fc
R-I)-/CD16 (Fc
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
)+/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-
-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 Peyers 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
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-
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
R-I (CD64)+ (=
CD14+/CD16-) Mo.
 |
MO SUBSETS IN PATHOPHYSIOLOGICAL CONDITIONS
|
|---|
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
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
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-
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
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-
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-
-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-
, 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
|
|---|
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-
-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
|
|---|
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
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
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
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-
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
R-I [97
] expression, and IL-2 release by activated
T cells [98
], the high IFN-
-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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