Absence of Major Histocompatibility Complex Class I on Neural Stem Cells Does No - 《stemcells》2004-2005文献干细胞之家



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a Department of Microbiology and Immunology and9 x. I  G; J/ k4 B2 Q1 I) F1 S$ |
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b Department of Neurosurgery, University of Miami School of Medicine, Miami, Florida, USA
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Key Words. Neural stem cells ? T-cell recognition ? Natural killer recognition Myosin heavy chain expression ? Cytotoxicity7 O3 P" c$ g# r! a  z! o

Correspondence: Robert B. Levy, Ph.D., University of Miami School of Medicine Department of Microbiology and Immunology, P.O. Box 016960 (R-138), Miami, FL 33101, USA. Telephone: 305-243-4542; Fax: 305-243-6903; e-mail: rlevy@med.miami.edu) t" \4 j/ v* C$ [! R+ W
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ABSTRACT

Stem cell populations can be identified in the central nervous system (CNS) of both embryonic and adult mammals, including mice . These neural stem cell (NSC) populations have the capacity to produce both neuronal and glial progeny in vitro, including neurons, astrocytes, and oligo-dendroglial cells . In addition, several studies have reported that murine and human NSCs have the potential to transdifferentiate and produce hematopoietic and other progeny . However, several groups have challenged these results . Furthermore, hematopoietic stem cell (HSC) transdifferentiation into nonhematopoietic cells is also an extremely rare event, and the results have not been reproduced . Notably, in vivo transdifferentiation in murine experiments was reported following transplant into allogeneic myosin heavy chain (MHC) disparate recipients . One question that arises following transplant of any progenitor population is how such cells will be surveyed by the recipient immune system. Because both T cells and natural killer (NK) cells have the potential to reject foreign progenitor cell populations , the expression of cell-surface MHC gene products is presumed to be a crucial factor in transplant outcome.4 l6 p+ h, `7 l; q$ i* i: y
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Although the absence of MHC expression on the cell surface of a transplanted population may protect against T-cell recognition, the inability to signal inhibitory receptors (i.e., Ly49 and KIR) may result in immune attack by autologous or allogeneic NK populations . The ability to evade both adaptive and innate systems in the recipient could support the initial engraftment of stem cell populations, although maintenance of differentiated MHCs expressing progeny may require different regulatory processes. Recent studies have reported that NK cells do not readily lyse embryonic stem cells , and previous investigations failed to detect NK and T cell–mediated killing of hematopoietic stem cell populations . CNS-derived cell populations, including neurons and oligodendroglial cells, express almost undetectable MHC class I and II products . The present studies assessed the constitutive and regulated expression of MHC products in embryonic-derived NSCs before analysis of their susceptibility to killing by cytotoxic T lymphocyte (CTL) and NK population. The findings demonstrated that the absence of MHC class I and II expression by early and later passaged NSCs protects the cells from immune recognition by allospecific CD8  CTL. However, upregulation of MHC class I on these stem cells enables their efficient recognition and lysis by CTL. Nonetheless, the absence or presence of MHC expression did not result in NSC susceptibility to lysis by either syngeneic or allogeneic NK cells. Such findings suggest that stem cells may not be readily killed by T/NK cells via the principal cell-mediated lytic effector pathways. The findings are discussed in relation to how stem cell populations may evade and inhibit immune graft rejection responses after transplant., b3 b) ?9 \" e

MATERIALS AND METHODS" l7 A4 w' U. I$ j/ t7 \

FGF2-expanded neuroepithelial stem cell cultures were established as neurospheres from E13 mouse cerebral cortex. The neurospheres were immunopositive for the neuroepithelial stem cell marker  nestin (Fig. 1B) and negative for neuronal and macroglia markers (data not shown). Upon plating onto an adherent substrate and serum, the cells differentiate into neurons (stained for type III beta-tubulin, a neuronal marker), oligodendrocytes (stained for O1, an oligo-dendroglial marker ), and astrocytes (stained for glial fibrillary acidic protein , an astrocytic marker)  (Figs. 1C, 1D), indicating that the neurospheres had the capacity to differentiate along the main CNS lineages. Continuous passage of neurospheres were obtained following dissociation and reculturing in noncoated dishes. Cells from neurospheres up to 17 passages were used in the experiments reported in this study. Transplant of stem cell populations requires host conditioning to facilitate donor cell engraftment and inhibits immune-mediated rejection by the recipient . To investigate the expression of MHC molecules on NSCs, freshly obtained B6 (H-2b) cortical cells from E13 embryos were incubated with directly conjugated anti-MHC class I and II mAbs. Flow cytometric analysis failed to detect staining with either H-2Kb–specific or H-2IAb–specific mAbs, indicating the absence of detectable cell-surface MHC proteins on these CNS cells (Fig. 2A). Subsequently, cells from NSC cultures (grown either with FGF2 or FGF2) and EGF (P2 and P15) were also found to lack expression of MHC class I and II products (Fig. 2 and data not shown). IFN is known to modulate MHC class I and II expression in mammalian cells , including neuroepithelial cells . To determine if IFN could upregulate MHC antigens in these cells, we incubated NSC (P2) for up to 60 hours in different concentrations of rmIFN before staining with the anti-MHC class I–specific and II–specific mAbs. After incubation with rmIFN concentrations ranging from 3–30 ng/ml, both MHC class I and II products were readily upreg-ulated in these cultures (Figs. 2C, 2D). MHC class I and II were also upregulated on long-term passaged cells, i.e., P9 to P15 (data not shown).4 l* H0 X- \- O" ?8 t

Figure 1. Stem cells from neurospheres give rise to all three central nervous system–derived cell types. (A): Phase contrast of P3 mouse neurospheres. (B): Double fluorescence labeling of P3-undifferentiated neurospheres showing immunoreactivity of N-cadherin in green and nestin in red. (C): P3-differentiated neurospheres were immunostained for type III beta-tubulin (green), a neuronal marker, and GFAP (red), an astrocytic marker. (D): P3-differentiated neurospheres were immunostained with 01 (yellow), an oligodendroglial marker, and GFAP (green). Note the yellow color is due to carbocyanine 3 emission spectrum and not due to overlay. Nuclei were revealed with 4,6-diamidino-2-phenylindole-2-HCI (blue). Abbreviation: GFAP, glial fibrillary acidic protein.
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Figure 2. Histograms from B6 E13 cortical cells (A) and B6 NSC P-15 (B) show a lack of MHC class I or class II staining. Solid black histograms represent unstained background. Cells stained with MHC class Ia H-2Kb-PE antibody or MHC class IIa H-2IAb-PE antibody are represented by the unfilled histogram. (A): Unstained background MFI = 2.3, class I MFI = 2.9, and class II MFI = 2.6. (B): Unstained background MFI = 3.0, class I MFI = 4.2, and class II MFI = 3.7. P2 B6 NSCs show upregulation of MHC class I (C) and class II (D) by mrIFN after culture for 60 hours. Solid histograms represent cells cultured with no IFN and stained with the appropriate antibody; class I MFI = 12, class II MFI = 22. Solid line histograms represent cells cultured for 60 hours with 3ng/ml IFN; class I MFI = 303, class II MFI = 77. Dashed line histograms represent cells cultured for 60 hours with 10 ng/ml IFN; class I MFI = 366, class II MFI = 114. Dotted line histograms represent cells cultured for 60 hours with 30 ng/ml IFN; class I MFI = 352, class II MFI = 147. Abbreviations: MFI, mean fluroescence intensity; MHC, major histocompatibility complex; mrIFN, recombinant murine interferon-gamma; NSC, neural stem cell.

To ensure that treatment of NSC cells with rmIFN did not lead to their differentiation into CNS cells and thereby account for the expression of MHC genes, these cultures were stained with markers that define cells derived from the neuroepithelium. Individual cells in P4 neurospheres are clearly detected by costaining for both N-cadherin and nestin (Figs. 3A, 3D). After coculture with rmIFN, type III beta-tubulin (a neuronal marker), RIP (an oligodendroglial marker), and GFAP (an astrocytic marker) were assessed (Fig. 3). These NSC cultures maintained in the presence or absence of IFN contained low or undetectable numbers of type III beta-tubulin  (middle panels) RIP  (middle panel), and GFAP  (right panels) populations. Notably, nestin continued to be expressed after rmIFN coculture at levels equivalent to NSCs not exposed to the cytokine (right panels). These findings demonstrate that after incubation with rmIFN, the NSC cultures did not differentiate toward neuronal, oligodendroglial, or astrocytic lineages.0 R% |% }" f$ V0 R

Figure 3. Confocal images show that the neurosphere characteristics and properties do not change after exposure to INF. Neu-rospheres that were exposed for 60 hours to recombinant murine INF (D, E, F) or not exposed (A, B, C) were stained with several markers to ensure that the cells did not differentiate. (A, D): Double fluorescence labeling of P4-untreated and -treated neurospheres showing immunoreactivity of N-cadherin in green and nestin in red. (B, E): P4-untreated and -treated neurospheres were immunos-tained with polyclonal type III beta-tubulin (green) or monoclonal anti-RIP (red). (C, F): Double-fluorescence labeling of P4-untreated and -treated neurospheres with a polyclonal anti-GFAP (green) and monoclonal anti-nestin (red). Note the absence of GFAP  cells in these neurospheres. Abbreviations: GFAP, glial fibrillary acidic protein; INF, interferon-gamma.
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Recognition by CD8  CTL requires expression of MHC class I products on target cells. Alloantigen reactive CTL from BALB/c spleen cells (H-2d) was generated after in vitro stimulation with B6 (H-2b)-stimulating cells and then assayed against B6 NSC cells obtained from early and later (data not shown) passaged cultures. The CTL effectively lysed control class I expressing EL4 (H-2b) target cells but failed to kill B6 P2 NSC targets (Fig. 4A). However, after incubation with rmIFN, as described above, the NSC target cells were efficiently lysed by the anti-H-2b CTL (Figs. 4A, 4B). Identical results have been obtained with all early and later passaged NSC cultures examined (data not shown). These observations confirmed the phenotypic absence of MHC class I on NSCs and indicated that such stem cells are unlikely to be recognized by host CTL after allogeneic transplant unless these products are upregulated on the stem cell population. Correlation of NSC susceptibility to lysis and MHC expression by the cells was confirmed in an independent experiment in which P2 NSC target cells expressing lower levels of MHC following rmIFN culture were not killed as effectively as the control H-2b target cells in the lytic assay (Fig. 4B).

Figure 4. Alloreactive cytotoxic T lymphocytes fail to lyse untreated NSC populations but kill mrIFN-treated NSC target cells. BALB/c spleen cells cultured with irradiated B6 spleen cells (anti-H-2b) for 5 days lyse EL4 (control H-2b target) () and B6 P2 NSCs treated with rmIFN (30 ng/ml, see Materials and Methods) () but not untreated B6 P2 NSCs (). (A, B): Differences in the amount of NSC target cell killing correlated with the amount of MHC class I upregulation on the NSC targets after rmIFN treatment (histogram insets, A and B, MHC expression assessed using anti-H-2Kb-PE monoclonal antibody). Abbreviations: MHC, myosin heavy chain; mrIFN, recombinant murine interferon-gamma; NSC, neural stem cell.
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The lack of MHC expression on the NSCs in the present studies would not enable inhibitory signaling by Ly49 receptors. Therefore, NK cell populations from syngeneic B6 and B6-SCID donor mice were tested to examine their ability to kill NSCs. As expected, these effector cells readily killed the NK-sensitive YAC-1 target cells but failed to lyse rmIFN-induced MHC class I–positive B6 NSCs (Figs. 5A, 5B). However, these NK cells also failed to lyse NSC target cells, which did not express detectable MHC class I (Figs. 5A, 5B). To determine if NK effector cells from allogeneic mice had the capacity to recognize B6 NSCs, spleen cells were assessed from normal and BALB/c-SCID mice for cytotoxic activity against NSC. Similar to the results using syngeneic populations, NK killing by this allogeneic population also exhibited strong killing against the YAC-1 target but did not lyse the NSC targets regardless of the absence (or presence) of MHC class I (Fig. 5C). Finally, in an independent experiment, an enriched B6 NK1.1  population was prepared by positive selection (see Materials and Methods), and the cells were activated for 24 hours with rIL-2 before use in a cyto-toxic assay (Fig. 5D). This population exhibited extremely potent killing activity against the NK-sensitive YAC-1 target cells but did not lyse the NSC targets.0 v) `0 Y+ C- f4 E, G+ b$ c4 G+ T
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Figure 5. Syngeneic and allogeneic NK cells do not kill early- or late-passaged NSC target cells. (A): Syngeneic B6 splenic NK cells lysed YAC-1 (control NK-sensitive target) () but not untreated P2 NSCs () or rmIFN-treated (as described in Fig. 4) P2 NSCs (). (B): Enriched syngeneic B6 NK spleen cells (Miltenyi DX5 beads: 74% NK1.1 , see Materials and Methods) lysed YAC-1 () but not untreated P-15 NSCs () or rmIFN-treated P-15 NSC (). (C):Allogeneic BALB/c (H-2d) splenic NK cells (5.6% DX5 , see Materials and Methods) lysed YAC-1 () but not untreated P-6 NSCs () or mrIFN-treated P-6 NSCs (). (D): Enriched syngeneic B6 NK cells (Miltenyi DX5 beads: 56.0%, see Materials and Methods) were placed into culture in medium supplemented with recombinant mouse interleukin-2 for 24 hours before assay (see Materials and Methods). Cultures were harvested, and the activated NK cells efficiently lysed YAC-1 () but not untreated P15 NSCs ().Abbreviations: mrIFN, recombinant murine interferon-gamma; NK, natural killer; NSC, neural stem cell.
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DISCUSSION, {0 L1 V) T5 G; j2 g
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This work was supported in part by NIH Grants 1R01 RR11576 and 5RO1 HL52461 (R.B.L.), NIH Grant N01-NS-6-2349, The Miami Project to Cure Paralysis, The FaBene Foundation, Wilson Foundation, and Abramson Foundation (P.T.). We acknowledge Karen Del Rio for her careful preparation of this manuscript and the Sylvester Comprehensive Cancer Center for its support of the Flow Cytometry Facility for the phenotypic analysis of cell populations used in these experiments.

Michele Mammolenti and Shyam Gajavelli contributed equally to this study.
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REFERENCES/ k8 K) f; Y- B5 c% p& S
; Q7 Z8 p! Z, w2 K
Anderson DJ. Stem cells and pattern formation in the nervous system: the possible versus the actual. Neuron 2001; 1:19–35.+ P% ^' l1 ]4 O2 p

Taupin P, Gage FH. Adult neurogenesis and neural stem cells of the central nervous system in mammals. J Neurosci Res 2002;69:745–749.
7 m5 L2 L$ \1 a
Mckay R. Stem cells in the central nervous system. Science 1997;276:66–71.1 w) e( b7 M9 A5 b9 u5 E  ]  G
; F, \& Q0 h& J) S: q# a# w
Bjornson CRR, Rietze RL, Reynolds BA et al. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 1999;283:534–537.6 [: K2 a! b  x7 S0 n: H: {% }( k
. \7 v+ j* J( C
Shih CC, Weng Y, Mamelak A et al. Identification of a candidate human neurohematopoietic stem-cell population. Blood 2001;98:2412–2422.; V  b, V7 m3 n) j6 @' N4 d
# X" \/ E. ^0 p
Galli R, Borello U, Gritti A et al. Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci 2000;3:986–991.

Clarke DL. Generalized potential of adult neural stem cells. Science 2000;288:1660–1663.
8 l+ J, l) X" s6 S6 ?. |" X; E0 p
Morshead CM, Benveniste P, Iscove NN et al. Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nat Med 2002;8:268–273.
) f. k# M7 o0 q" f
Magrassi L, Castello S, Ciardelli L et al. Freshly dissociated fetal neural stem/progenitor cells do not turn into blood. Mol Cell Neurosci 2003;22:179–187.
. H9 p( u) n. L( `
Yusta-Boyo MJ, Gonzalez MA, Pavon N et al. Absence of hematopoiesis from transplanted olfactory bulb neural stem cells. Eur J Neurosci 2004;19:505–512.
$ t- c, c+ B4 f9 E
Wagers A, Sherwood R, Christensen JL et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256–2259.
7 o% {3 o( \) x0 c
Murray CE, Soonpa MH, Reinecke H et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004;428:664–668.

Balsam LB, Wagers AJ, Christensen JL et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004;428:668–673.8 q0 J% e5 T( Q6 |- D2 \$ c
" p0 L8 @7 Z9 T* g6 L
Murphy WJ, Kumar V, Bennett M. Acute rejection of murine bone marrow allografts by natural killer cells and T cells: differences in kinetics and target antigens recognized. J Exp Med 1987;166:1499–1550.
; W8 [% ?: K& G) t
Takeda K, Moore MW, Dennert G. Acute rejection of marrow grafts in mice: dependence on an independence of functional TcR in the rejection process. J Immunol 1994;152: 4402.
0 V. j' v- p$ _5 E1 P
Davenport C, Kumar V, Bennett M. Rapid rejection of H2k and H2k/b bone marrow cell grafts by CD8  T cells and NK cells in irradiated mice. J Immunol 1995;155:3742.
: m* m$ l) P& O! b
Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 2002;20:217–251.6 S( A2 |# |9 s  a

Drukker M, Katz G, Urbach A et al. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A 2002;99:9864–9869.. ^$ v  S. g' a

Aguila HL, Weissman IL. Hematopoietic stem cells are not direct cytotoxic targets of natural killer cells. Blood 1996; 87:1225–1231.3 W" I1 M" T5 G0 t8 `2 `

Lampson, LA. Interpreting MHC class I expression and class I/class II reciprocity in the CNS: reconciling divergent findings. Microsc Res Tech 1995;32:267–285.
5 |3 k1 O: k* L# M' z
Corriveau RA, Huh GS, Shatz CJ. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 1998;21:505–520.
- W, }* F+ W) S- U0 S0 Q, B
Theiler K. The House Mouse:Atlas of Embryonic Development. New York: Springer-Verlag,1989.* X8 R0 y/ w/ z- B. p

Reynolds BA, Weiss S. Colonal and populations analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 1996;175:1–13.
( w- t1 n4 U2 w/ B
Bingnami A, Eng LF, Dahl D et al. Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence. Brain Res 1972;43:429–435.9 i+ Z6 w  D/ }+ U9 l
, f4 p* b8 {4 o
Caccamo D, Katsetos CD, Herman MM et al. Immunohistochemistry of a spontaneous murine ovarian teratoma with neuroepithelial differentiation: neuron-associate beta-tubulin as a marker for primitive neuroepithelium. Lab Invest 1989;60:390–398.

Sommer I, Schachner M. Monoclonal antibodies (O1 to O4) to oligodendrocyte cell surfaces: an immunocytological study in the central nervous system. Dev Biol 1981;83:311–327.. u8 i8 k# u$ P. n/ B) x$ W3 o
( A- B; K8 s' F) e
Friedman B, Hockfield S, Black JA et al. In situ demonstration of mature oligodendrocytes and their process: an immunocytochemical study with a new monoclonal antibody, rip. Glia 1989;2:380–390.! N' i9 j5 {" i

Levy RB, Cray C, Jones M. HSV-1 enhances GvHR associated parent anti-F1 alloreactivity in vivo and in vitro. Cell Immunol 1990;129:1–12.
: D* q: X; |5 {8 F
Hockfield S, McKay RD. Identification of major cell classes in the developing mammalian nervous system. J Neurosci 1985;5:3310–3328.

Kernan NA, Bordignon C, Heller G et al. Graft failure after T-cell-depleted human leukocyte antigen identical marrow transplants for leukemia, I: analysis of risk factors and results of secondary transplants. Blood 1989;74:2227–2236.
0 M5 q& @, d% q, ?4 ?" C
Soiffer RJ, Mauch P, Tarbell NJ et al. Total lymphoid irradiation to prevent graft rejection in recipients of HLA nonidentical T cell-depleted allogeneic marrow. Bone Marrow Transplant 1991;7:23–33.
0 n1 I2 z2 b) C4 s7 t$ H+ _  c
Khouri IF, Keating M, Korbling M et al. Transplantlite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998;16:2817–2824.
: ?0 I* p6 X( q( Y4 G  _
Geppert TD, Lipsky PE. Antigen presentation by interferon-g-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression. J Immunol 1985;135:3750–3762.
' w0 D6 a& d) s8 \8 w
Pober JS, Collins T, Gimbrone MA et al. Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens inducted by recombinant immune interferon. Nature 1983;305:726–729.
! `2 F, c+ ]2 i+ n/ Z. h4 r
Wong GHW, Clark-Lewis I, Harris AW et al. Effect of cloned interferon-g on expression on H-2 and Ia antigens on cell lines of hemopoietic, lymphoid, epithelial, bibroblastic and neuronal origin. Eur J Immunol 1984;14:52–57.

Krampera M, Glennie S, Dyson J et al. Bone marrow mes-enchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003;101:3723–3729.
' B0 X) J" i) O1 R9 F9 ~& Q, o  G
Bailey KA, Drago J, Bartlett PF. Neuronal progenitors identified by their inability to express class I histocompatibility antigens in response to interferon-gamma. J Neurosci Res 1994;39:166–177.( ?! G! Q+ u% z8 ?4 p

Kimura S, Tada N, Nakayama E et al. Studies of the mouse Ly-6 alloantigen system, I: serological characterization of mouse Ly-6 alloantigen by monoclonal antibodies. Immunogenetics 1980;11:373–381.
0 P$ m% t0 R7 k5 t
Cray C, Keane RW, Malek TR et al. Regulation and selective expression of Ly-6A/E, a lymphocyte activation molecule, in the mouse central nervous system. Mol Brain Res 1990;8:9–15.  S7 Z, D# J$ k0 R
3 [8 N  `$ X: Z$ D* x
Bartholomew A, Sturgeon C, Siatskas M et al. Mesenchy-mal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002;30:42–48.

Gur H, Krauthgamer R, Berrebi A et al. Tolerance induction by megadose hematopoietic progenitor cells: expansion of veto cells by short-term culture of purified human CD34  cells. Blood 2002;99:4174–4181.
) [; `/ q7 ~- }. j4 N6 n. |( k
Alenzi FQ, Marley SB, Lewis JL et al. A role for the Fas/Fas ligand apoptotic pathway in regulating myeloid progenitor cell kinetics. Exp Hematol 2002;30:1428–1435.2 q8 a$ C' ]- z& U" Q8 H& M
( N% _( L7 {+ i2 L) k
Ng WF, Duggan PJ, Ponchel F et al. Human CD4 CD25  cells: a naturally occurring population of regulatory T cells. Blood 2001;98:2736–2734.; M8 j2 o) ?/ m7 I2 D
- i% V3 ?" R2 h" v4 r9 E7 ]
Karanu FN, Murdoch B, Gallacher L et al. The notch ligand jagged-1 represents a novel growth factor of human hema-topoietic stem cells. J Exp Med 2000;192:1365–1372.9 g) I$ S7 J& T8 n8 Z- v- s
1 Y# p* E, o: L+ Z1 m8 I' f: q  o
Varnum-Finney B, Purton LE, Yu M et al. The Notch ligand, Jagged-1, influences the development of primitive hema-topoietic precursor cells. Blood 1998;91:4084–4091.4 o+ f) l" G9 K( [4 v- n# k( T

Baker MB, Podack ER, Levy RB. Perforin- and Fas-mediated cytotoxic pathways are not required for allogeneic resistance to bone marrow grafts in mice. Biol Blood Marrow Transplant 1995;1:69–73.5 ~+ t4 k2 o( f1 ~3 K. k

Aguila HL, Hershberger RJ, Weissman IL. Transgenic mice carrying the diptheria toxin A chain gene under the control of the granzyme A promoter: expected depletion of cytotoxic cells and unexpected depletion of CD8 T cells. Proc Natl Acad Sci U S A 1995;92:10192–10196.& P# t$ D+ z) X2 m, i$ f/ n) M
* C. f3 h3 S) p& R
Graubert TA, Russell JH, Ley TJ. The role of granzyme B in murine models of acute graft-versus-host disease and graft rejection. Blood 1996;87:1232–1237.2 V5 b: i* {1 F5 C

Komatsu M, Mammolenti M, Jones M et al. Antigen-primed CD8  T cells can mediate resistance preventing allogeneic marrow engraftment in the simultaneous absence of perforin, CD95L, TNFR1 and TRAIL. Blood 2003;101:3991–3999.2 v+ ?; M5 n) Y/ f& H$ f6 L3 o+ Y0 L
2 x, ~9 {& u$ O# }
Hori J, Ng TF, Shatos M et al. Neural progenitor cells lack immunogenicity and resist destruction as allografts. STEM CELLS 2003;21:405–416.(Michele Mammolentia, Shya)

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