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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-02-0653.
IMMUNOBIOLOGY
From the Immunobiology and Cancer Program, Oklahoma
Medical Research Foundation, Oklahoma City; and the Department of
Pathology, University of Chicago, IL.
Recent studies have demonstrated that lineage marker-negative
(Lin Natural killer (NK) cells have long been recognized
for their importance in innate immunity, viral defense, and tumor
surveillance.1 Additionally, NK cells represent barriers
to bone marrow transplantation and produce cytokines that influence
other cellular components of the immune system. Impressive progress has
recently been made in understanding how NK cells recognize targets for
cytolytic destruction while sparing normal cells.2 For
example, it is now clear that self-tolerance of NK cells is maintained
by inhibitory receptors, which are expressed on NK cells and recognize
major histocompatibility complex (MHC) class I molecules. In mice, the Ly49 receptor family recognizes classical MHC I molecules, whereas the
CD94/NKG2 receptors recognize the nonclassical Qa-1b MHC I
molecule. Some additional NK molecules have been suggested to function
as activating receptors.3 Recent reports suggest that the
self-recognizing NK-cell receptor repertoire is built in successive
fashion following contact of NK-cell precursors with environmental
class I MHC molecules during development.3,4 However, many
questions remain about the origin and lifespans of NK cells. Although
still incomplete, a differentiation sequence is emerging that will
eventually describe how hematopoietic stem cells generate NK cells in
mice and humans.5 Although cells with NK-lineage potential
can be found among undifferentiated thymocytes, and some properties are
shared with T cells, the thymus is probably not the most important site
for production of NK cells.6,7 The present study was
designed to obtain more precise information about relationships between
early NK-lineage precursors and those of other lymphoid lineages within
bone marrow.
The NK-1.1 antigen encoded by the NKR P1C gene
provides a useful NK-cell marker in selected strains of mice,
but is also expressed on a subset of T cells (NK T cells). The DX5
antigen, recently shown to be identical to CD49, is somewhat less
restricted to NK-lineage cells,8 and is probably acquired
at a later stage. For example, there are NK-1.1+
DX5 Although interleukin 2 (IL-2) can be used to drive formation of NK
cells in vitro, IL-2-deficient mice and IL-2 receptor Kondo and colleagues24 demonstrated that a category of
Lin Serum-free, stromal cell-free cultures containing recombinant Flt3
ligand (FL), stem cell factor (SCF), and IL-7 have been described that
efficiently support the differentiation of CLP/early pro-B cells to
CD19-bearing B-lineage lymphocytes.26,29 We now show that
addition of a fourth cytokine, IL-15, stimulates the formation of
immature NK cells in these cultures. In addition to B and T
lymphocytes, NK cells derive from rare hormone-regulated precursors in
bone marrow. The acquired resistance of maturing NK precursors to
estrogen provides a means of establishing when B and NK lineages
diverge in bone marrow. This important event seems to occur within the
early pro-B/CLP fraction coincident with, or just prior to, acquisition
of the IL-15 receptor. These findings should be helpful for further
analysis of mechanisms that coordinately and then independently
regulate production of B and NK lymphocytes.
Mice
Antibodies
Reagents Recombinant mouse IL-7 was purchased from Endogen (Woburn, MA). Recombinant mouse IL-15 was purchased from Research Diagnosis (Flanders, NJ). Recombinant mouse SCF and mouse FL were purchased from R & D Systems (Minneapolis, MN). 1,3,5[10]-Estratriene-3, 17 -diol
(-estradiol, E2) was purchased from Sigma Chemical (St Louis, MO).
Isolation of Lin  ) and supplemented with 3% fetal
calf serum (FCS). Cells were incubated with antibodies to lineage
markers (Gr-1 and Mac-1 for myeloid cells, anti-CD19 and anti-CD45RA
for B-lineage cells, and TER-119 for erythroid cells) for 20 minutes.
Then cells were washed and incubated with magnetic-activated
cell-sorted (MACS) goat anti-rat IgG microbeads (Miltenyi Biotec,
Bergisch Gladbach, Germany) for 15 minutes. Bead-labeled cells were
depleted using MACS separation columns and a magnet following the
manufacturer's instructions. These enriched lineage marker-negative
bone marrow cells were then stained with a cocktail of labeled
antibodies to the lineage markers (FITC-conjugated anti-CD2, anti-CD3,
anti-CD8, anti-Gr-1, anti-Mac-1, PE-conjugated TER-119 anti-DX5,
anti-CD19, and anti-CD45R/B220) and APC-conjugated anti-c-kit
antibody. In some experiments, PE-labeled anti-Flk-2/Flt3 antibody and
biotinylated anti-IL-7R antibodies were also used. In this case,
PE-labeled TER-119 and DX5 antibodies were eliminated and
FITC-conjugated anti-CD19 and anti-CD45R were used instead of
PE-conjugated ones. Phycoerythrin-Texas red tandem-conjugated
streptavidin (streptavidin-PE-TR; Caltag, Burlingame, CA) was used as
the secondary reagent for biotinylated anti-IL-7R. Stained cells
were sorted on a MoFlo (Cytomation, Ft Collins, CO). When reanalyzed
after sorting, Lin cells were generally more than
95% pure, that is, less than 5% had even slightly above background
levels of staining. Subsets of these Lin cells were
usually more than 90% pure when sorted according to absence, low
density, or high density of c-kit. The IL-7R+ cells were
relatively homogenous, but the IL-7R preparations
included some cells with low, but above threshold, staining. In some
experiments, LinLo/ cells were simply enriched by MACS
separation. In those cases, antibodies to anti-CD2 for NK cells and
anti-CD3 for T cells were added to the lineage marker cocktail.
Cell culture Sorted cells were put into 24-well culture plates (Costar, Cambridge, MA) containing 1 mL X-VIVO15 medium (Biowhittaker, Walkersville, MD) containing 1% detoxified bovine serum albumin (Stem Cell Technologies, Vancouver, BC, Canada), 5 × 10 5 M
2-mercaptoehtanol (2-ME), 2 mM L-glutamine, 100 U/mL
penicillin, 100 mg/mL streptomycin, and cytokines as indicated and
cultured at 37°C and 5% CO2 in a humidified atmosphere.
The concentrations of cytokines were IL-7, 1 ng/mL; FL, 100 ng/mL; SCF,
20 ng/mL; and IL-15, 50 ng/mL. Seven days later, cells were harvested;
cell numbers and viability were determined with a trypan blue dye
exclusion method and then subjected to flow cytometry analysis. For
single-cell sorting experiments, cells were directly sorted into wells
of 96-well U-bottom tissue culture plates (Costar) containing 100 µL
of the same media. Individual wells were harvested 11 to 15 days later
and analyzed by flow cytometry. For 2-step culture experiments, cells
were first cultured with IL-7, FL, and SCF for 5 days and then washed
and split into 2 cultures with either IL-7 alone or IL-15 alone for
another 5 days. In 2-step sorting experiments, cells were first
cultured with IL-7, FL, and SCF for 3 days before staining with
anti-CD19, anti-CD11b/Mac-1, anti-CD45R, and anti-CD122.
CD19 Mac-1 cells were sorted into 4 subsets
according to the expression of CD45R and CD122 and cells in each subset
were cultured with SCF, FL, IL-7, and IL-15 for another 5 days.
Immunofluorescence staining For the analysis of surface antigens, cells were incubated with combinations of labeled antibodies in PBS supplemented with 3% FCS. They were then washed and incubated with PE-Texas red tandem-conjugated streptavidin to detect biotinylated primary antibodies. Stained cells were run on a FACScalibur flow cytometer (Becton Dickinson, San Diego, CA) and the data were analyzed with FlowJo software (Treestar, San Carlos, CA).Hormone treatment in vivo Time-release pellets of 17-estradiol (0.1 mg/pellet, 21-day
release; Innovative Research of America, Sarasota, FL) were implanted subcutaneously with a 10-gauge precision trochar. After 7 days, mice
were killed and bone marrow progenitor cells were sorted.
Formation of immature NK cells from lymphocyte precursors in culture Previous studies have demonstrated that the c-kit tyrosine kinase receptor is progressively down-regulated as hematopoietic stem cells give rise to early lymphocyte precursors.31 Therefore, we used this characteristic to subdivide the Lin fraction of
bone marrow and assessed each for the potential to generate NK-lineage
lymphocytes in culture. Preliminary experiments established that in
addition to CD43+CD45R+CD19+
B-lineage lymphoid cells, DX5-bearing cells efficiently emerged when
IL-15 was added to serum-free medium that also contained SCF, FL, and
IL-7.20,26 These DX5+ lymphocytes lacked CD3
and we examined a series of other markers associated with conventional
NK cells. Although there are significant numbers of
CD3DX5+ NK-1.1 cells in spleens
of C57BL/6 mice, most of the DX5+ cells that emerged in
culture coexpressed NK-1.1 (Figure 1). The CD94 receptor was expressed on a subset of culture-generated NK
cells but the Ly49G2 receptor typically expressed by mature NK cells
was not detected (Figure 1). Although all Lin fractions
contained at least some precursors for these immature NK cells, careful
analysis of the yield per input cell revealed enrichment among the
c-kitLo subset (Figure 2).
The c-kitLo cells represent 24% of the total
Lin fraction of bone marrow, whereas 62% are
c-kitHi and 14% are c-kit.31
Even when adjusted on this basis, most of the precursors that can
generate NK cells within 1 week of culture are Lin
c-kitLo. Longer intervals and addition of a fifth cytokine,
either megakaryocyte growth and development factor (MDGF) or
IL-3, increased the yield of NK cells from the c-kitHi
fraction (data not shown). Also, it is important to note that no NK
cells emerged when IL-15 was the only cytokine and addition of DX5 to
the cocktail of antibodies used for lineage depletion had no effect on
the results (data not shown). This indicates that the cell suspensions
used to initiate our cultures were not contaminated with NK cells whose
receptors were modulated during handling. We conclude from these
experiments that immature NK cells can be efficiently generated in
stromal cell-free, serum-free cultures containing only recombinant
cytokines. Most precursors that differentiate within 1 week of culture
reside in the same Lin c-kitLo fraction that
contains CLP/early pro-B cells.
NK- and B-lineage lymphocytes both derive from estrogen-sensitive precursors Our previous studies showed that functional B-lymphocyte precursors within the Lin c-kitLo fraction
are depleted when estrogen levels are high.26,28 There is
a corresponding loss of phenotypically defined CLP/early pro-B cells,
providing strong evidence that this is the major differentiation
pathway for lymphocyte production. It was therefore important to learn
if NK cells are made in similar fashion. The Lin
c-kitLo fraction was recovered from mice treated for 1 week
with time-release estrogen pellets and used to initiate NK cultures.
Elevated hormone levels only slightly reduced numbers of
Lin c-kitLo cells (data not shown), but
functional precursors of both B- and NK-lineage cells were dramatically
depleted (Figure 3). It is highly likely
that both categories of lymphocytes derive from hormone-regulated
Lin c-kitLo precursors.
Identification of precursors with restricted NK-differentiation potential The experiments described above revealed an important similarity between B- and NK-cell precursors but were not informative about whether they have a common origin within the Lin
c-kitLo fraction. We previously found that early pro-B
cells are directly sensitive to estrogen and experiments were done to
see if the same was true for NK progenitors.26 As
expected, the hormone inhibited generation of B-lineage cells (Figure
4). Absolute numbers of CD19+
cells recovered from estrogen-containing cultures averaged 26% of
those present in control cultures in 9 experiments. However, production
of NK-lineage cells in the same cultures was more resistant to the
hormone (averaged 56% of control values).
These findings could be most easily explained in terms of heterogeneity
within the Lin
In summary, the Lin Cytokine receptor expression and responsiveness mark NK-lineage progression Four recombinant cytokines were used to support the expansion and maturation of cells in our cultures, and acquisition of functional receptors for those agents can represent useful milestones of differentiation.33 As noted above, IL-15 was required for efficient NK-lineage differentiation, but NK cells did not emerge when cultures of Lin c-kitLo cells contained IL-15
alone. Further experiments were conducted to learn more about when
precursors of the B and NK lineages become independently regulated by
these positive stimuli. Lin c-kitLo cells
were sorted and placed in bulk cultures containing SCF, FL, and IL-7
for 5 days. The cells were then harvested, washed, and cultured for an
additional 5 days in the presence of either IL-7 alone or IL-15 alone
(Figure 6). It is clear that progression in the B and NK lineages was independently controlled by these 2 factors.
The Lin
Similar experiments were done to explore the timing of acquisition of
the IL-2R
Additional experiments were done with the 2-step culture system to
learn when NK-lineage cells become hormone insensitive. Cultures were
initiated with an enriched fraction of LinLo/ The IL-7 knockout mice have reduced numbers of NK cells34
and the cytokine enhanced production of DX5+ cells in our
cultures (data not shown). On the other hand, IL-7 is not thought to be
essential for generation of NK cells in vivo.35,36 This
accords with our finding that a substantial number of NK precursors do
not display the IL-7R. Furthermore, B and NK lineages diverge at some
point and can be independently driven by IL-7 and IL-15, respectively.
Our results are compatible with a differentiation sequence where
acquisition of the IL-15R corresponds with loss of B-lineage potential.
Given the heterogeneity of precursors within the Lin
Although substantial progress has been made in identifying early
lymphocyte precursors, important questions remain about when the NK
lineage diverges from those corresponding to other blood cell types.
Our findings support and extend previous studies in showing that the
largest population of NK-cell precursors is contained within an
estrogen-sensitive, Lin Similarities with respect to cytotoxic capability and sharing of some surface markers suggest that T and NK cells may be closely related.37 Early precursors for NK and other lymphoid lineages can be found in the double-negative 1 fraction of the adult thymus.38 Furthermore, clonal assays were used to detect bipotential T/NK progenitors in the fetal thymus.6,39 However, NK cells develop normally in athymic mice and other evidence suggests that most NK cells are normally produced in the bone marrow.7 The selective dependence of NK cells on the Ets-1 transcription factor and the Id-2 transcriptional repressor, as well as their relative independence from PU.1, are additional indications of their separation from the T-lymphocyte lineage.40-42 For these reasons, the focus of our study was on NK-cell precursors in bone marrow. A series of previous studies suggested that an intact bone marrow microenvironment is required for differentiation of marrow precursors to functional NK cells.43 Some of those experiments used osteopetrotic mice that were treated for prolonged periods with high doses of estrogen. The hormone sensitivity of early lymphocyte precursors we have now found must be a consideration in the interpretation of such experiments. However, the new results do not detract from the overall conclusion that bone marrow is a principal site for NK-cell generation. The immature NK cells previously discovered in the spleens of osteopetrotic mice are likely similar to the estrogen-resistant CD122+ NK precursors described here.20 However, it is remarkable that functional maturation did not occur until the cells were isolated from that environment and stimulated with IL-15, an event that normally occurs within bone marrow. Furthermore, marrow destruction by the marrow-seeking isotope strontium 89 (89Sr) was also accompanied by functional NK deficiency.43 We conclude from these and other studies that the marrow environment is particularly well suited to the production and maturation of NK-cell precursors. Early stages in that process may be regulated by hormones. Although acquisition of the full repertoire of NK-cell receptors
requires interaction in trans with stromal
cells,4,33 we found it possible to generate immature
CD3 Because of their low abundance, early lymphohematopoietic precursors
are usually studied in suspensions that have been depleted of lineage
marker-bearing cells. We used CD3, CD8, Mac-1/CD11b, Gr-1/Ly-6G,
TER-119, CD45R/B220, CD19, DX5, and CD2 antigens for this purpose and
then further separated marrow cells according to the density of c-kit.
Previous studies have shown that long-term repopulating stem cells and
very early precursors are present in the c-kitHi
fraction.28,31,44 As just one indication of their position in the lineage, substantial time is required for Lin Magnetic bead separation and high-speed sorting now make it possible to
isolate many subsets of blood cell precursors and test their
differentiation potential. However, it can be difficult to arrange them
into a sequence corresponding to normal bone marrow. We used 2 hormone
treatment strategies to determine that the Lin One previous study demonstrated that at least 1 of 20 Lin Environmental cues required for generation of early lymphocyte
precursors remain poorly understood. They are present in
IL-7R Progression of cells in the 2 lineages is independently driven by IL-7
and IL-15, respectively. Both cytokines use receptors containing
Our findings suggest that sex steroids negatively control production of
early precursors corresponding to all lymphoid lineages. We previously
found that estrogen and androgen receptors are down-regulated as cells
progress from Lin It must be stressed that our experiments were conducted with adult marrow and NK-lineage differentiation pathways may be different during embryonic life. As in the case of our adult marrow experiments, acquisition of CD122 signals restriction of NK-precursor fate in fetal thymus.6 However, fetal and neonatal NK cells express high levels of CD94/NKG2A receptors, but not Ly49. Subsequently, CD94/NKG2A gradually declines as the Ly49 family of receptors are acquired.10 Although single cells with restricted lymphoid potential are present in adult marrow 9,24,26,46 (and this report), B/T-cell precursors have not been detected in fetal tissues.57 Furthermore, we have recently found that early lymphocyte precursors do not acquire functional receptors for sex steroids until after birth.53 It will be extremely important to learn if fetal and adult lymphocytes derive from separate pools of stem cells or pathways of differentiation. Many details remain about when and how early precursors of NK cells become distinct from those corresponding to other blood cells. However, the present findings provide a better framework for understanding this process. Gene-targeting experiments should reveal precisely when particular factors such as Ets-1 and Id-2 are required, whereas studies on cell labeling should now be performed to learn about population dynamics, turnover rates, and NK-cell lifespans.
The authors thank Dr Lisa Borghesi for critical reading of the manuscript, Ms Viji Dandapani for cell sorting, and Dr Takafumi Yokota for experimental help and suggestions.
Submitted February 28, 2002; accepted June 21, 2002.
Prepublished online as Blood First Edition Paper, July 5, 2002; DOI 10.1182/blood-2002-02-0653.
Supported by grant AI20069 and AI33085 from the National Institutes of Health. P.W.K. holds the William H. and Rita Bell Chair in biomedical research.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Paul W. Kincade, Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK 73104; e-mail: kincade{at}omrf.ouhsc.edu.
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  K. Maeda, A. Malykhin, B. N. Teague-Weber, X.-H. Sun, A. D. Farris, and K. M. Coggeshall Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals Blood, May 7, 2009; 113(19): 4534 - 4540. [Abstract] [Full Text] [PDF]
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R. S. Welner, R. Pelayo, K. P. Garrett, X. Chen, S. S. Perry, X.-H. Sun, B. L. Kee, and P. W. Kincade Interferon-producing killer dendritic cells (IKDCs) arise via a unique differentiation pathway from primitive c-kitHiCD62L+ lymphoid progenitors Blood, June 1, 2007; 109(11): 4825 - 4931. [Abstract] [Full Text] [PDF]
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L. L. Veinotte, C. P. Greenwood, N. Mohammadi, C. A. Parachoniak, and F. Takei Expression of rearranged TCR{gamma} genes in natural killer cells suggests a minor thymus-dependent pathway of lineage commitment Blood, April 1, 2006; 107(7): 2673 - 2679. [Abstract] [Full Text] [PDF]
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E. Fronkova, O. Krejci, T. Kalina, O. Horvath, J. Trka, and O. Hrusak Lymphoid Differentiation Pathways Can Be Traced by TCR {delta} Rearrangements J. Immunol., August 15, 2005; 175(4): 2495 - 2500. [Abstract] [Full Text] [PDF]
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K. Maeda, Y. Baba, Y. Nagai, K. Miyazaki, A. Malykhin, K. Nakamura, P. W. Kincade, N. Sakaguchi, and K. M. Coggeshall IL-6 blocks a discrete early step in lymphopoiesis Blood, August 1, 2005; 106(3): 879 - 885. [Abstract] [Full Text] [PDF]
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L. Borghesi, L.-Y. Hsu, J. P. Miller, M. Anderson, L. Herzenberg, L. Herzenberg, M. S. Schlissel, D. Allman, and R. M. Gerstein B Lineage-specific Regulation of V(D)J Recombinase Activity Is Established in Common Lymphoid Progenitors J. Exp. Med., February 17, 2004; 199(4): 491 - 502. [Abstract] [Full Text] [PDF]
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L. Borghesi and R. M. Gerstein Developmental Separation of V(D)J Recombinase Expression and Initiation of IgH Recombination in B Lineage Progenitors In Vivo J. Exp. Med., February 17, 2004; 199(4): 483 - 489. [Abstract] [Full Text] [PDF]
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T. Yokota, C. S. R. Meka, T. Kouro, K. L. Medina, H. Igarashi, M. Takahashi, K. Oritani, T. Funahashi, Y. Tomiyama, Y. Matsuzawa, et al. Adiponectin, a Fat Cell Product, Influences the Earliest Lymphocyte Precursors in Bone Marrow Cultures by Activation of the Cyclooxygenase-Prostaglandin Pathway in Stromal Cells J. Immunol., November 15, 2003; 171(10): 5091 - 5099. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
chain (
/