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The Distinct Surface of Human Blood Dendritic Cells, As Observed After An Proc. Nail. Acad. Sci. USA Vol. 87, pp. 7698-7702, October 1990 Immunology The distinct surface of human blood dendritic cells, as observed after an improved isolation method (mixed leukocyte reaction/antigen presentation/colony-stimulating factor 1 receptor/leukocyte integrins/CD45R molecule) PETER S. FREUDENTHAL AND RALPH M. STEINMAN The Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021 Communicated by Maclyn McCarty, June 28, 1990 (received for review May 10, 1990) ABSTRACT Prior studies have identified a subset of den- Cell Separation. See Fig. 1. Granulocytes were isolated dritic cells in human blood, as well as their stimulatory function from heparinized whole blood (13) and used immediately. For for T-cell-mediated immune responses. However research has mononuclear cells, the blood or leukocyte-enriched "buffy been limited by difficulties in isolation, since dendritic cells coat" was layered onto Ficoll-Paque (1.0777 g/ml; Pharma- make up only 0.1-1% of blood mononuclear cells. We present cia) and sedimented at 1000 x g for 20 min at 21°C. Mono- a protocol that reliably yields preparations that are >80-90% nuclear cells were harvested from the interface and sedi- pure. The method relies on the sequential depletion of the mented three times in phosphate-buffered saline (PBS) with- major cell types in blood and simultaneously provides T cells, out Ca2' and Mg2+ to remove platelets (first at 650 x g then monocytes, and B plus natural killer cells for comparison with twice at 235 x g). T lymphocytes were separated by rosetting dendritic cells. The last step in the procedure is the removal of at 4°C with neuraminidase-treated sheep erythrocytes fol- residual contaminants on the basis of expression of a CD45R lowed by Ficoll-Paque sedimentation. T cells were recovered epitope. The enrichment of dendritic cells is evident by three from the pellet by lysing the erythrocytes in NH4Cl and criteria, each of which is related to the surface of these washing twice in RPMI 1640 (6). The T-cell-depleted eryth- antigen-presenting cells. (i) All dendritic cells are motile, rocyte rosette-negative (ER-) fraction was washed twice in constantly forming large lamellipodia or veils. (ii) When ana- RPMI 1640 and cultured at 3-5 x 106 cells per ml at 37°C for lyzed with a large panel of monoclonal antibodies and the 36 hr in 100-mm tissue culture dishes. After culture, most of FACS, the cells express high levels of all known polymorphic the cells could be collected from the plates. By reculturing the major histocompatibility complex gene products, as well as a cells twice for 30-40 min at 37°C on fresh dishes, the distinct combination of receptors and adhesion molecules. monocytes were selectively attached. Nonadherent cells Unlike monocytes, for example, dendritic cells lack Fc recep- were "panned" once or twice on bacteriologic plastic dishes tors and the colony-stimulating factor 1 receptor (c-fms) but coated with human immunoglobulin to remove residual Fc express much higher levels of ICAM-1 and LFA-3 adhesins. fragment receptor (FcR)-bearing monocytes (6). To recover (iii) In functional assays, dendritic cells are at least 100 times the adherent monocytes, the dishes were washed three times more potent than monocytes or lymphocytes in stimulating the with cold PBS and cultured with fresh medium for 3-4 hr, at primary mixed leukocyte reaction. These properties help make which point the monocytes were easily dislodged from the the trace subset of dendritic cells more amenable to further surface. The monocyte- and T-cell-depleted fraction (5-8 x functional and clinical studies. 106 cells per ml; 3-4 ml) was layered onto 2.5-ml columns of hypertonic 14.5% metrizamide (dissolved in RPMI 1640 with have described dendritic 10% heat-inactivated fetal calf serum) in 15-ml conical tubes Prior reports (1-9) antigen-presenting and sedimented at 650 x g for 10 min at room temperature cells in human blood. These cells resemble more extensively (14). The dendritic-cell-enriched interface was separated studied counterparts in the lymphoid tissues of other species. from the B- and natural killer (NK)-cell-enriched pellet. Both In particular, blood dendritic cells express high levels ofmajor fractions were washed in two successively less hypertonic histocompatibility complex (MHC) products and actively washes to return the cells to isotonicity [RPMI 1640 supple- stimulate primary T-cell responses to transplantation antigens mented with 10% fetal calf serum and 40 mM NaCl (wash 1) (3, 4, 10-12). When we began to study dendritic cells in or 25 mM NaCl (wash 2)]. individuals infected with human immunodeficiency virus type CD45R Panning. The dendritic cell fraction was treated 1, we encountered difficulties in obtaining sufficiently high with a monoclonal antibody (mAb) specific for restricted purity and in monitoring the purification. To date, only partial CD45 antigen (CD45R) (Leul8; Becton Dickinson) at 20 ,ul of purification of dendritic cells (<1% of blood mononuclear mAb per 106 cells in 1-2 ml of culture medium and on ice for cells) has been achieved, and there has been no detailed study 45-60 min. The cells were washed four times and sedimented with the fluorescence-activated cell sorter (FACS). Here we twice at 50 x g (5 min, 4°C) onto plastic dishes coated with present an approach for preparing highly enriched popula- goat antibodies to mouse immunoglobulin (10). The plates tions, which we then study to describe their distinctive mo- were swirled gently prior to harvesting the dendritic cell tility, phenotype, and function. preparation that was depleted of CD45R+ contaminants. Cel Sorting. An alternative final step in the dendritic cell METHODS enrichment procedure was to use the FACS. Cells in the metrizamide low-density fraction were combined with 20 ,ul of Culture Medium. RPMI medium 1640 supplemented with fluorescein-conjugated Leui8 per 106 cells in 1-2 ml ofmedium 5-10% heat-inactivated normal human AB' serum, 1 mM on ice for 45-60 min. The cells were washed four times and glutamine, 50 ,uM 2-mercaptoethanol, penicillin at 100 units/ ml, and streptomycin at 100 ,ug/ml was used. Abbreviations: MHC, major histocompatibility complex; ER, eryth- rocyte rosette; NK, natural killer; mAb, monoclonal antibody; MLR, The publication costs of this article were defrayed in part by page charge mixed leukocyte reaction; APC, antigen-presenting cell(s); FcR, Fc payment. This article must therefore be hereby marked "advertisement" fragment receptor; C3R, complement component 3 receptor; IL-2R, in accordance with 18 U.S.C. §1734 solely to indicate this fact. interleukin 2 receptor; CSF, colony-stimulating factor. 7698 Downloaded by guest on September 25, 2021 Immunology: Freudenthal and Steinman Proc. Natl. Acad. Sci. USA 87 (1990) 7699 PROTOCOL MEAN CELL YIELDS Mixed Leukocyte Reaction (MLR). Stimulators (antigen- [RANGE] presenting cells, APC) for the MLR were derived from the (Whole blood or Buffy Coats ) A B separation protocol. The APC were irradiated [3000 rads (1 rad = 0.01 from and added in doses to 1.5 U Ficoll-Hypaque Column (from 6 expts.1 [from 6 expts.1 Gy) '37Cs] graded x 105 allogeneic or syngeneic T cells in 96-well flat-bottom tissue culture in 0.2 ml of medium well. Prolifer- ~Boom plates per ononucler cells 5.6x108 5.8x108 ation was measured by the uptake of [3H]thymidine [1 p.Ci per [4.3 6.81 [4.8- 7.61 Sheep Erythrocyte Rosette well, 6 Ci/mmol (1 Ci = 37 GBq)] added for 8 hr on the 5th day. The responses are reported as the mean cpm of tripli- T,Tcell enriched) 2.3x108 2.2x108 cates, omitting the standard deviations, which were <10%. l d etd Rosette (+) [1.5 - 3.11 [1.3 - 3.31 Motility and Morphology. Morphology and motility were monitored at 370C on an incubated-stage inverted microscope Tcell with a video a video cassette depleted] 2.2x108 (Nikon Diaphot) camera, Rosette (-) 2.6x108 recorder, and monitor attached. [1.0 - 3.01 12.0 - 3.51 1) 36 hours Culture 2) Serial Plastic Adherence RESULTS 3) Human Ig Panning Method and Monitoring Criteria for Enriching Human LI Blood Dendritic Cells. Fig. 1 outlines a sequence of steps that Monocyte & T cell 9.0 x 107 6.7 x 107 enriched the trace Depleted Population reliably population of human blood den- [2.0 - 13.01 [4.4 - 9.81 dritic cells. Using protocol A, we obtained 3.5 x 106 cells that Metrizamide Column were 30-60% dendritic cells. Protocol B allows further enrichment (80-90%) by using the CD45R panning method B and NK cells 7.3x107 5.3x107 discussed below. At the same time, three other dendritic were obtained: T cells (Lesit DHigh Density [1.8 -10.01 [3.5 - 8.01 cell-depleted populations by erythro- cyte rosetting, monocytes by plastic adherence after 1-2 days 6 in a [ow Density DC-Enriched 5.2x10 4.5x106 culture, and mixture of B and NK cells by sedimentation [3.5- 7.01 [2.9 - 6.01 in metrizamide (Fig. 1). Two were Final UCD45R approaches used to document the progressive Plastic E Panning enrichment of dendritic cells. First, observation of live prep- Adherence 1X arations best revealed an irregular shape and motility, as outlined below. Second, cytofluorography displayed the en- 3.5x106 2.4x106 richment of large cells (high forward scatter) that failed to Final DC Eniched a 12.2 - 4.6] [1.4 - 3.21 stain with cocktail ofmAbs to other types ofleukocyte (Fig. Population- 2: CD14, monocytes; CD16 and CD56, NK cells; CD19 and CD20, B cells; and CD3, T cells).
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