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TRANSPLANTATION
From the Department of Medicine, Division of Immunology
and Rheumatology, and the Department of Pathology, Stanford University
School of Medicine, CA.
The "conventional" NK1.1 Mature T-cell receptor Although regulatory NK1.1+ T cells in the marrow can
suppress immune responses of NK1.1 In the current report, the surface phenotype, cytokine secretion
profile, and function of highly purified NK1.1 Mice and monitoring of GVH disease
BCL1 tumor cell passage and injection
Monoclonal antibodies; immunofluorescent staining and flow cytometric analysis BM cells were obtained from the femur and tibia and stained with mAbs as described previously.2,5 Stainings were performed in the presence of anti-CD16/32 (2.4G2, Pharmingen) at saturation to block FcRII/III receptors, and propidium iodide (Sigma Chemicals, St Louis, MO) was added to staining reagents to exclude dead cells. Three-color FACS analysis was performed using a modified dual laser FACS Vantage (Becton Dickinson, Mountain View, CA), and data were analyzed using FACS/Flow Jo software (Becton Dickinson).14 The following conjugated antibodies were used for staining: fluorescein isothiocyanate (FITC)-anti-CD8 (CT-CD8 ) and streptavidin-Texas Red
purchased from Caltag, South San Francisco, CA; and allophycocyanin- and phycoerythrin (PE)- and FITC-anti-TCR (H57-597),
PE-anti-NK1.1 (PK136), FITC-anti-CD4 (RM4-5), FITC-anti-CD44 (IM7),
unconjugated anti-CD16/CD32 (2.4G2), FITC-anti-CD45.2 (104), FITC-
and PE-anti-H-2Kb (AF6-88.5), PE-anti-B220 (RA3-6B2),
PE-anti-Gr-1 (RB6-8C5), PE-anti-MAC-1 (M1/70), FITC-anti-CD62L
(MEL-14), and FITC-anti-CD45RB (16A) purchased from Pharmingen.
APC-anti-CD4 and APC-anti-CD8a were gifts from Dr Irving Weissman's
laboratory at Stanford. FITC-anti-BCL1-Id (6A5.1) mAb was
obtained from hybridoma supernatants and conjugated as described
previously.12
Sorting of blood and BM T cells The CD4+, CD8+, and CD4+/CD8+TCR+
(NK1.1+ or NK1.1 ) T cells from the blood or
marrow were obtained by flow cytometry using FACStar or FACS Vantage
(Becton Dickinson) after enrichment of blood and marrow T cells on
immunomagnetic bead columns (Miltenyi, Auburn, CA) as described
previously.2,5 The stringently T-cell-depleted (TCD)
marrow cells (CD4CD8/)
were also obtained by flow cytometry as described
previously.5
Liver and gut lymphocyte preparation After hosts were exsanguinated, livers were flushed with heparinized phosphate-buffered saline in the right ventricle until the liver became pale. Livers were pressed through a nylon mesh to prepare single-cell suspensions in 2 µM ethylenediaminetetraacetic acid in phosphate-buffered saline. The cell suspension was centrifuged on Ficoll-Hypaque, and the interface layer was collected for lymphocyte staining. Gut, including duodenum through rectum, was collected, cut longitudinally, and rinsed thoroughly with cold RPMI 1640. The rinsed gut was put into ethylenediaminetetraacetic acid in phosphate-buffered saline, minced into smaller than 5 mm segments, and suspended by vortex 20 to 30 seconds. After 3 repeats, cells in the supernatant were filtered through a nylon mesh before separation on a Ficoll-Hypaque gradient for collection of mononuclear cells.In vitro secretion and measurement of cytokines Sorted T cells (1 × 105) from the blood or BM were stimulated in vitro with 20 ng/mL phorbol myristate acetate (Sigma Chemicals) and 1µM ionomycin (Calbiochem, San Diego, CA) in 10% fetal bovine serum and RPMI complete medium in 96-well round bottom plates and harvested at the peak time point (48 hours) as described previously.2,5,15 Supernatants were assayed for the secretion of IL-2, IFN- , IL-4, and IL-10 using commercial
enzyme-linked immunosorbent assay kits (Biosource, Camarillo,
CA).2,5,15
Histopathology of skin and large intestine Histopathologic specimens from the skin and large intestines of hosts were obtained at 40 to 60 days or 100 days after transplantation and fixed in formalin before embedding in paraffin blocks. Tissue sections were stained with hematoxylin and eosin and examined at 400× magnification.Statistical analysis Differences in survival of groups of hosts given BM transplants were analyzed using the log-rank test. Differences in donor-type T-cell recovery in tissues of hosts were analyzed using the 2-tail Student t test.
Different patterns of surface receptor expression on CD4+ and CD8+ T cells from blood and BM Our previous studies showed that NK1.1+ T cells make up about 30% to 50% of TCR+ T cells in the marrow
but only about 1% in the blood.2,5 NK1.1+ T
cells have been previously reported to be
CD44hiCD45RBhi.4 In the current
study, we studied the expression of CD44 on the NK1.1+ and
NK1.1 CD4+ and CD8+ T cells from
blood and marrow by multicolor flow cytometry after staining with mAbs.
As shown in Figure 1A, 26.4% of blood
mononuclear cells were CD4+TCR+ T cells.
The mean (± SE) percentage in 4 mice was 23% ± 2%. After gating
on the CD4+TCR+ cells, only 0.8% of the
cells were found to be NK1.1+, and 99.2% were
NK1.1 (Figure 1B; mean 0.7% ± 0.1% and
99.3% ± 0.1%, respectively). TCR+CD4+ cells were gated into
NK1.1+ and NK1.1 cells for single-color
analysis of CD44. Blood NK1.1 CD4+ cells were
found to be mostly CD44int/lo (Figure 1C, open profile,
left panel). CD4+TCR+ cells accounted for
0.4% of cells in the marrow (Figure 1A), and 25.4% of them were
NK1.1+, and 74.6% were NK1.1 (Figure 1B;
mean 27% ± 1% and 73% ± 2%, respectively). In contrast to
blood NK1.1 CD4+ cells, most of the marrow
NK1.1 CD4+ cells were CD44hi
(Figure 1C, shaded profile, left panel). About 16.3% of PB mononuclear cells were CD8+TCR+ cells (Figure 1A;
mean 13% ± 2%). Only 0.9% of the latter cells were
NK1.1+ (mean 1.0% ± 0.2%), and there were insufficient
PB NK1.1+ CD8+ cells for further analysis. Most
blood NK1.1 CD8+ cells were also
CD44int/lo (Figure 1D, open profile, left panel).
TCR+CD8+ cells in the marrow accounted
for 1.1% of nucleated cells (Figure 1A), and 15.8% were
NK1.1+ (mean 0.9% ± 0.2% and 18% ± 1%,
respectively). In contrast to the blood NK1.1
CD8+ cells, most NK1.1 CD8+ cells
were CD44hi (Figure 1D, shaded profile, left
panel).
Because CD44 is expressed at high levels in early T-cell development in
the thymus and on activated/memory T cells,16,17 the
expression of CD62L and CD45RB was studied also. The latter markers are
down-regulated on activated/memory cells and present at higher levels
on naive T cells.18,19 As shown in Figure 1D, both blood
and marrow NK1.1 Different cytokine secretion profiles of CD4+ and CD8+ T cells from blood and BM To study the cytokine secretion profiles of the blood and marrow T-cell subsets, all T cells were first enriched with immunomagnetic beads, and desired subsets were thereafter isolated with flow cytometry. Sorted subsets (100 × 103) were stimulated with phorbol myristate acetate and calcium ionophore in vitro for 48 hours. The culture supernatants were assayed with enzyme-linked immunosorbent assay for the concentration of IL-2, IFN-, IL-4, and
IL-10. As shown in Table 1, sorted blood
CD4+ T cells (> 99% NK1.1) produced large
amounts of IL-2 (mean 2856 pg/mL) but little IFN- (mean 78 pg/mL),
IL-4 (mean 26 pg/mL), or IL-10 (mean 17 pg/mL). In contrast, sorted
marrow CD4+ T cells containing about 25%
NK1.1+ cells (Figure 1) produced about 5 times less IL-2
but 10 times more IFN- and 20 times more of the Th2 cytokines IL-4
and IL-10. The sorted marrow NK1.1 CD4+ T
cells still produced 7-fold less IL-2 but about 10 times more IFN-,
IL-4, and IL-10 as compared with the sorted blood CD4+ T
cells. Marrow CD4+ NK1.1+ T cells produced
small amounts of IL-2 (mean 355 pg/mL) and large amounts of IFN-
(mean 1051 pg/mL), IL-4 (mean 3072 pg/mL), and IL-10 (mean 380 pg/mL).
When the relative concentrations of IL-2, IFN-
Comparison of cytokine profiles from blood CD8+ T (99%
NK1.1 Differences in the function of CD4+ and CD8+ T cells from blood and BM in the GVH disease assay Because blood and marrow CD4+ and CD8+ T-cell subsets had markedly different surface receptor expression and/or cytokine secretion profiles, we tested their function in a model of GVH disease using major histocompatibility complex-mismatched C57BL/6 (H-2b) donors and BALB/c (H-2d) hosts.5 Graded numbers of sorted blood and marrow T-cell subsets from the donor mice were coinjected with 1.5 × 106 stringently TCD donor marrow cells into lethally irradiated 8 Gy (800 rads) hosts. As shown in Figure 2A, all the recipients given TCD marrow cells alone survived for more than 100 days without any signs of GVH disease, and the recipients given no TCD marrow cells all died by day 14 (data not shown). Addition of graded numbers (25 × 103-500 × 103) of sorted blood CD4+ T cells induced severe diarrhea, weight loss, and mortality in a dose-dependent manner but no hair loss. The survival was significantly reduced as compared with that of the recipients given TCD marrow alone (P < .001, log-rank test). In contrast, addition of 500 × 103 sorted marrow CD4+ (NK1.1+ and NK1.1) T cells induced no
clinical signs of GVH disease, and all the recipients survived for more
than 100 days (Figure 2A). Furthermore, addition of
500 × 103 marrow NK1.1 CD4+ T
cells induced only transient and mild signs of GVH disease, such as
slight diarrhea and weight loss between days 40 to 60 after
transplantation (data not shown), and all hosts survived for more than
100 days.
The colon and skin tissues were harvested from moribund recipients
given blood CD4+ T cells between days 45 to 60. For
comparison, tissues from recipients given marrow CD4+ or
NK1.1
The capacity of blood and marrow CD8+ T-cell subsets to
induce GVH disease were compared also. As shown in Figure 2B, TCD
marrow cells alone induced no GVH disease, but addition of
500 × 103 blood CD8+ T cells induced severe
GVH disease, and 70% of the recipients died within 100 days. Addition
of 100 × 103 blood CD8+ T cells still
induced typical clinical signs of GVH disease, but only 10% of the
recipients died (Figure 2B). In contrast, addition of
500 × 103 marrow CD8+ (NK1.1+
and NK1.1 Different tissue distribution of blood and marrow CD4+ and CD8+ T cells in irradiated allogeneic hosts To distinguish donor cells derived from the injected blood or marrow T cells from those derived from the TCD marrow cells, blood CD4+/CD8+ or marrow CD4+/CD8+ T cells (500 × 103) from C57BL/6 (H-2b, CD45.2) mice were coinjected with TCD marrow cells (1.5 × 106) from congenic C57BL/6 mice (H-2b, CD45.1) into lethally irradiated BALB/c recipients (H-2d, CD45.2). Seven days later, the mononuclear cells from blood, gut, spleen, liver, and marrow were harvested and stained with anti-TCR, anti-H-2b, and anti-CD45.2 mAbs.
Figure 4 shows the percentage of injected
donor T cells and/or their progeny among the mononuclear cells from
different tissues of the BALB/c recipients. About 20% of the blood
mononuclear cells from the recipients given sorted blood
CD4+/CD8+ T cells and TCD marrow cells were
donor-type T cells (TCR
The mean percentages and yields of donor-type T cells from different
tissues are shown in Table 3. The mean
absolute numbers of the donor-type T cells in blood, gut, and spleen
from the recipients given blood CD4+/CD8+ T
cells were found to be respectively 40-fold (P < .001),
20-fold (P < .001), and 2-fold (P < .05)
higher than that in the recipients given marrow
CD4+/CD8+ T cells. However, there was no
significant difference (P > .1) in the livers and marrow
of the 2 kinds of recipients. These results indicate that the marked
difference in the capacity of blood and marrow
CD4+/CD8+ T cells to induce GVH disease is
associated with their markedly different early expansion in the blood
and gut tissues of the recipients.
Function of BM CD4+ and CD8+ T cells in graft versus tumor and facilitation of engraftment assays To test the antitumor activity of marrow CD4+ and CD8+ T cells, graded numbers of sorted T cells were coinjected with 1.5 × 106 C57BL/6 Rag-2/
marrow cells and 60 BCL1 B cell lymphoma cells into
lethally irradiated (8 Gy [800 rads]) BALB/c recipients. As shown in
Figure 5A, all the irradiated recipients
given 1.5 × 106 Rag-2/ marrow cells
alone survived for more than 100 days, but all the recipients given the
same dose of marrow cells in combination with 60 BCL1 cells
died of tumor growth by day 43. In contrast, addition of sorted marrow
CD8+ T cells to the RAG-2/ marrow cells
increased the survival in a dose-dependent manner. Addition of as few
as 25 × 103 marrow CD8+ T cells allowed 10%
of the recipients to survive for more than 100 days
(P > .05, log-rank test). Addition of
100 × 103 and 500 × 103 marrow
CD8+ T cells, respectively, allowed 40% and 100% of the
recipients to survive for more than 100 days (P < .0001).
The spleen cells of the recipients were stained with
anti-BCL1-Id mAb and analyzed by flow cytometry for the
presence of BCL1 cells. The spleens of moribund recipients
given only RAG-2/ marrow cells contained 50% to 80%
of BCL1 cells (data not shown). The spleen cells of 2 of
the 4 recipients given 100 × 103 marrow CD8+
T cells and RAG-2/ marrow cells that survived for more
than 100 days had 5% to 10% BCL1 cells, and the spleens
of recipients given 500 × 103 marrow CD8+ T
cells had no detectable BCL1 cells (data not shown). The
results indicate that high doses of marrow CD8+ T cells are
able to eliminate the BCL1 cells, but low doses induce "tumor dormancy."
As shown in Figure 5B, addition of 100 × 103 marrow
NK1.1+CD8+ T cells showed little antitumor
activity. In contrast, addition of marrow NK1.1 Although marrow CD4+ T cells alone were not able to mediate antitumor activity, they enhanced the antitumor activity mediated by marrow CD8+ T cells. As shown in Figure 5D, 100 × 103 combined marrow CD4+/CD8+ T cells were able to effectively treat hosts given BCL1 cells, and all the recipients survived for more than 100 days. In contrast, 100 × 103 sorted marrow CD8+ T cells alone rescued only 40% of the BCL1-bearing recipients (Figure 5A,D, P < .01, log-rank test). In addition, the survival of the recipients given 25 × 103 or 6.25 × 103 marrow CD4+/CD8+ T cells was similar to that of the recipients given 100 × 103 or 25 × 103 marrow CD8+ T cells, respectively (Figure 5A,D, P > .05, log-rank test). We did not test the antitumor activity of either blood CD4+ or CD8+ T cells, because these cells induced lethal GVH disease. The sorted marrow CD4+ and CD8+ T cells were
also tested for facilitation of engaftment of hematopoietic
progenitors. Graded numbers of marrow CD4+ or
CD8+ T-cell subsets were coinjected with a suboptimal dose
(750 × 103) of C57BL/6 donor TCD marrow cells into
lethally irradiated BALB/c recipients without tumor cells. As shown in
Figure 6A, only 10% of the recipients
given TCD marrow cells alone had long-term survival of more than 100 days. Addition of marrow CD8+ T cells to the TCD marrow
cells resulted in a dose-dependent increase in long-term survival.
Injection of as few as 6.25 × 103 marrow
CD8+ T cells increased the long-term survival from 10% to
30% (P < .05, log-rank test), and
25 × 103 marrow CD8+ T cells increased the
long-term survival to 70% (P < .001, log-rank test).
Further increase of the marrow CD8+ T-cell dose to
100 × 103 or 500 × 103 failed to further
increase the survival beyond this plateau (Figure 6A).
In contrast, addition of 500 × 103 marrow
CD4+ T cells or C57BL/6xBALB/c F1 marrow CD8+ T
cells did not increase the survival rate as compared with TCD marrow
alone (Figure 6B). As shown in Figure 6C, the spleen cells of the
recipients were stained with anti-H-2b versus TCR
In the current study, the NK1.1 The unusual surface receptor phenotype of marrow CD4+ T
cells was associated with an atypical cytokine secretion profile. Blood CD4+ T cells produced large amounts of IL-2 with little
IFN- We tested the blood and BM CD4+ and CD8+ T
cells for their function in 3 different assay systems: (1)
induction of GVH disease, (2) mediation of allogeneic
antitumor activity, and (3) facilitation of engraftment of
allogeneic hematopoietic progenitors. Separated donor blood
CD4+ and CD8+ T cells induced lethal GVH
disease, whereas separated donor T-cell subsets from the marrow failed
to induce lethal GVH disease, including all CD4+, all
CD8+, NK1.1 Consistent with previous reports,10-12 the current study
showed that marrow CD8+ T cells mediated antitumor activity
and facilitated engraftment of donor hematopoietic stem cells but
failed to induce GVH disease even at high cell numbers
(500 × 103). At lower doses, peripheral CD8+
T cells have been reported to mediate antitumor activity without GVH
disease.27,28 Antitumor activity was mediated by the
NK1.1
We thank Jun-Chuan Xu and Aditi Mukhopadhyay for their excellent technical assistance and Mary Hansen for her assistance in preparation of manuscript.
Submitted July 11, 2001; accepted October 3, 2001.
Supported with funds from National Institutes of Health grants HL-57443 and HL-58250.
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: Samuel Strober, Division of Immunology and Rheumatology, Department of Medicine, CCSR Bldg, 2215-C, Stanford Medical Center, 300 Pasteur Dr, Stanford, CA 94305-5166; e-mail: sstrober{at}stanford.edu.
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B. J. Chen, X. Cui, G. D. Sempowski, C. Liu, and N. J. Chao Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease Blood, February 15, 2004; 103(4): 1534 - 1541. [Abstract] [Full Text] [PDF]
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 P. Hoffmann, J. Ermann, M. Edinger, C. G. Fathman, and S. Strober Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation J. Exp. Med., August 5, 2002; 196(3): 389 - 399. [Abstract] [Full Text] [PDF]
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 M. C. Walters, A. W. Nienhuis, and E. Vichinsky Novel Therapeutic Approaches in Sickle Cell Disease Hematology, January 1, 2002; 2002(1): 10 - 34. [Abstract] [Full Text]
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
surface immunoglobulin
phenotype.
channel 1) or intermediate (channel 1-10) levels, and
the remainder expressed high (
channel 10) levels of CD45RB.
Two-color analysis of CD44 versus CD62L or CD44 versus CD45RB on the
latter cells revealed that 30% to 50% had an unusual CD44hiCD62LhiCD45RBint/hi phenotype
similar to the marrow NK1.1
