By
From the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892
B cells are susceptible to Fas ligand (FasL)+ CD4+ Th1 cell-mediated apoptosis. We demonstrate that blocking the interactions between lymphocyte function associated (LFA)-1 and intercellular adhesion molecule(ICAM)-1 and ICAM-2 completely suppresses Fas-dependent B cell lysis. Antibodies to CD2 and CD48 partially suppress B cell apoptosis, whereas anti-B7.1 and anti-B7.2 antibodies have no effect. Also, B cells from ICAM-1-deficient mice are resistant to FasL+ T cell-mediated death. Our results suggest that LFA-1/ICAM interactions are crucial for Th1 cell-mediated B cell apoptosis and may contribute to the maintenance of B cell homeostasis in vivo.
Bcells are sensitive to apoptosis mediated by Fas (Apo-1/CD95; references 1). The importance of Fas in B
cell apoptosis is supported by B cell accumulation and autoantibody production in mice with defective Fas or Fas
ligand (FasL) genes or in humans with mutated Fas genes
(5). Although Fas-FasL interactions are important for T
cell apoptosis after TCR cross-linking, B cell apoptosis induced by cross-linking of the B cell antigen receptor does
not involve Fas (9), suggesting that B and T cells differ in
Fas-dependent apoptosis. Since FasL expression is undetectable in a variety of mouse and human B cell lines (9, 10), B cells are likely to depend on apoptotic signals
through Fas that are generated by interactions with FasL-bearing T cells (11, 12).
Fas-mediated signaling in B cells appears to be regulated
by the cell activation status. While resting B cells resist Fas cross-linking-induced death, mitogen-activated B cells are
susceptible to Fas-mediated killing (13). Cross-linking of
CD40 leads to upregulation of Fas expression and sensitivity to Fas-mediated apoptosis (14, 15). The roles of adhesion
molecules or accessory molecules have not been characterized in CD4+ T cell-mediated B cell lysis by the Fas pathway
(16). We examined the roles of accessory molecules in Fas-mediated B cell lysis. We found that the interactions of
LFA-1 on CD4+ T cells and intercellular adhesion molecule-1 and ICAM-2 on B cells are essential for the T cell-
mediated B cell lysis. Deficiency in ICAM-1 leads to decreased B cell apoptosis and the accumulation of B cells in
vivo.
Mice.
6-8-wk-old female C57BL/6, C57BL/6-ICAM-1 Antibodies, Fusion Proteins, and Peptides.
Anti-LFA-1 (M17.4),
anti-ICAM-1 (3E2), anti-ICAM-2 (MIC2/4), anti-B7.1 (1G10),
anti-B7.2 (GL1), anti-CD2 (RM2-5), anti-CD48 (HM48-1),
anti-Fas (Jo2), anti-CD4 (GK1.5), anti-CD8 (53-6.7), anti-Thy-1.2 (30-H12), anti-NK1.1 (PK136), anti-CD40 (3/12), anti-FasL, anti-CD16/32, PE conjugated anti-Fas, PE-conjugated
anti-ICAM-1, PE-conjugated anti-ICAM-2, FITC-conjugated
anti-LFA-1, FITC- or PE-conjugated anti-CD4, and PE-conjugated anti-CD3 were purchased from PharMingen (San Diego,
CA). FITC-conjugated F(ab Purification and Stimulation of B Cells.
Mouse spleen cells were
suspended in RPMI 1640 medium containing 20% FCS (5 × 106
cells/ml) and 10 ml cells were added to each 100 mm tissue culture dish. After incubation at 37°C for 1 h, nonadherent cells
were recovered and resuspended in HBSS medium (107/ml) containing 10 µg/ml of anti-Thy-1.2, anti-CD4, anti-CD8, and
anti-NK1.1 antibodies, and then incubated on ice for 45 min. Next, 1:10 low-tox-M rabbit complement (Accurate Chemical
and Science Corp., Westbury, NY) was added and the cells were
incubated at 37°C for 1 h. Live cells were purified by Ficoll gradient separation and between 95 and 98% of the cells were positive for surface IgM when stained with a PE-conjugated F(ab Stimulation of T Cells and 51Cr-release Assay.
A.E7 T cells were
stimulated with antigen and IL-2 as previously described (17). To
induce allo-specific CD4+ T cells, BALB/c spleen cells were suspended in RPMI complete medium containing 1 µg/ml FITC
conjugated anti-CD4 (107 cells/ml) and incubated on ice for 30 min. CD4+ cells were then purified with magnetic beads conjugated with sheep antifluorescein antibody (PerSeptive Diagnostics, Cambridge, MA). The CD4+ T cells were mixed with 3,000 Rad-irradiated C57BL/6 mouse spleen cells at a ratio of ~1:5
and suspended in RPMI complete medium (106 CD4+ T cells/
ml). After culture at 37°C for 5 d, live cells were purified and
used as effector cells to assay B cell lysis. For 51Cr-release assay, B
cells were incubated in RPMI medium containing 5% FCS (5 × 106/ml) and 200 µCi/ml Na[51Cr]O4 (New England Nuclear,
Boston, MA) with or without 10 µm antigenic peptide at 37°C
for 1 h followed by washing with HBSS three times. The labeled
B cells (104/well) were incubated with T cells in a total volume
of 200 µl in RPMI complete medium at various ratios in triplicates in 96-well U-bottomed plates (Nunc, Roskilde, Denmark).
Various antibodies, isotype-matched antibody controls, Fas-Fc,
or TNFR-Fc fusion proteins at 10 µg/ml were added as indicated. After 4 h incubation at 37°C, percentage cell loss was
quantitated as described (2).
Induction of B Cell Apoptosis with Anti-Fas.
B cells were suspended in RPMI complete medium (0.5 × 106 cells/ml) containing 1 µg/ml of Jo2 (anti-Fas) or control hamster IgG. The
cells (105/well) were cultured in 96-well flat-bottomed plates at
37°C for 24 h. Viable cells were quantitated and percentage of
cell loss was calculated as described previously (6).
Staining of Cell Surface Markers.
AE.7 cells were cultured in
RPMI complete medium (106/ml) with or without 3,000 Rad-irradiated B10A spleen cells (5 × 106/ml) and 10 µM pigeon cytochrome C peptide 88-104. A metalloproteinase inhibitor,
KBR8301 (18), was added to 10 µg/ml and the cells were cultured at 37°C for 6 h. The cells were then stained with PE-conjugated anti-FasL and FITC-conjugated anti-CD4 followed by
flow cytometry. CD4+ AE7 cells were gated to analyze FasL expression. To examine the expression of accessory molecules, B
cells were blocked by incubating with 10 µg/ml anti-CD16/32,
1:100 normal rat serum, and 10 µg/ml normal hamster IgG on
ice for 30 min. The cells were next stained with 1 µg/ml PE-conjugated anti-Fas, FITC-conjugated anti-LFA-1, PE-conjugated
anti-ICAM-1, or PE-conjugated anti-ICAM-2. Isotype-matched FITC- or PE-conjugated rat anti-CD4 or PE-conjugated hamster
anti-CD3 were used as negative controls. After incubation on ice
for 30 min, the cells were analyzed by flow cytometry.
We first tested the lysis of B cells by T cells in a
Th1-mediated cytotoxicity assay. We used either A.E7, a
CD4+ Th1 clone that recognizes pigeon cytochrome C
amino acids 88-104 presented by I-Ek (19), or allo-reactive
CD4+ T cells generated from an MLR. Resting B cells or
B cell blasts from either B10.A mice (I-Ek+) pulsed with
the pigeon cytochrome C peptide or B cells from C57BL/
6 mice were targets for A.E7 and the allo-reactive T cells, respectively. We found that A.E7 cells efficiently lyse B cell targets preactivated with either LPS or anti-CD40 but not
untreated resting B cells (Fig. 1 A). Blocking of Fas-FasL
interactions by Fas-Fc abolished the lysis of B cell targets
by A.E7 cells (Fig. 1 B), whereas TNFR-Fc, a blocker for
TNF action, did not interfere with B cell death (Fig. 1 B).
Similar results were obtained with allo-reactive CD4+ T
cells (Fig. 1, C and D). These data agree with previous
findings that lysis of target B cells by CD4+ T cells is predominantly Fas dependent (2). Antigen-specific recognition by T cells is required because A.E7 cells failed to lyse
target B cells that were not pulsed with antigen before the assay (reference 1 and data not shown). Thus, Th1-mediated cytotoxicity against B cells is Fas and antigen dependent.
We next tested mAbs to block accessory molecules in the T cell-mediated, B cell cytotoxicity assays. We
found that anti-LFA-1 completely blocked the killing of
target B cells by A.E7 (Fig. 2 A). Similar results were observed with allo-reactive T cells. B cell lysis was also significantly suppressed by anti-ICAM-1 but not by anti-
ICAM-2 alone (Fig. 2, A and B). Both anti-ICAM-1 and
anti-ICAM-2 together nearly completely suppressed B cell
apoptosis. Therefore, both ICAM-1 and ICAM-2 are involved in T cell-mediated B cell killing, but ICAM-1 appears to be more important.
In contrast, blocking mAbs to B7.1 and B7.2 had no effect on B cell lysis by CD4+ T cells (Fig. 2, A and B), although CD28 and B7 molecules are highly expressed on
the T and B cells used in these assays (data not shown).
This indicates that the CD28/B7 interaction is not involved in CD4+ T cell-mediated B cell killing. These results also suggest that the blocking of B cell lysis by other
antibodies is not simply a steric effect due to antibodies
bound to cell surface structures. We also examined CD2 on
T cells and CD48 on B cells, another receptor-ligand pair
important for T-B cell interactions in mice (20). We found that B cell lysis was inhibited by anti-CD2 and anti-CD48
(Fig. 2, A and B), but the effect was much weaker than by
blocking of LFA-1-ICAM interactions.
Our results suggested that their physical interaction, possibly by promoting Th1-B cell adhesion, was involved in
Th1-mediated B cell apoptosis. However, an alternative
possibility is that those mAbs may deliver a negative signal
into the cells and inhibit the killing process. We therefore
examined whether these mAbs influenced anti-Fas antibody-mediated B cell apoptosis. We first established conditions in which anti-Fas antibody efficiently lysed the B cells
(Fig. 2 C). We then added anti-LFA-1, anti-ICAM-1, anti-ICAM-2, anti-B7.1, anti-B7.2, anti-CD2, and anti-CD48 and found that none of these affected direct anti-Fas-mediated B cell lysis. Thus, these mAbs do not interfere with apoptotic signaling from Fas.
It remained possible that LFA-1-ICAM interactions in
our assay simply promoted T cell activation and FasL expression rather than facilitate Fas-FasL interactions leading
to death. To distinguish between these possibilities, we
studied freshly activated A.E7 cells that express more FasL
to see if the requirement for LFA-1-ICAM interactions
was less. However, anti-LFA-1 and anti-ICAM-1 still blocked B cell lysis by freshly activated A.E7 cells (Fig. 3). Flow cytometry showed that FasL was upregulated on
AE.7 cells immediately after antigen stimulation (Fig. 3).
This supports the hypothesis that LFA-1 and ICAM function
primarily to promote T-B cell adhesion for Fas-mediated B
cell apoptosis. Although anti-Fas antibodies induce rapid
formation of a death-inducing signaling complex linked to
the cytoplasmic portion of Fas, proteolytic processing and
activation of FLICE/caspase 8 requires up to 20 min of
continuous Fas cross-linking (21). This suggests that the activation of caspases essential for apoptosis requires certain period of stabilized engagement of Fas receptor. It is therefore reasonable to postulate that LFA-1-ICAM binding
promotes Fas signaling by enhancing FasL-Fas interactions
between T and B cells.
Stimulation of B cells with LPS or CD40 ligation sensitizes B cells for Fas-mediated apoptosis. This is at least partially due to Fas upregulation. Fig. 4 shows that both LPS
and anti-CD40 upregulated Fas as they sensitized B cells for
apoptosis. Concomitant with the sensitization for apoptosis,
we found that LPS and anti-CD40 induced significant upregulation of ICAM-1 on B cells, whereas LFA-1 was
slightly increased and ICAM-2 was not changed at all. Thus, the induction of both Fas and ICAM-1 on B cells by
stimuli such as LPS and anti-CD40 may make B cells vulnerable to apoptosis mediated by FasL+ T cells.
We also tested the cytotoxic effect of
MLR-derived CD4+ T cells on B cells prepared from mice
homozygously deficient for ICAM-1. Wild-type and
ICAM-1
Since the interactions of LFA-1 and ICAM-1 and
ICAM-2 are important for the lysis of B cells in vitro, we
asked whether they contribute to B cell homeostasis in
vivo. We found no abnormality in the B cell compartment
in relatively young ICAM-1
/
,
B10.A, and BALB/c mice were obtained from the Jackson Laboratory (Bar Harbor, ME).
)2 goat anti-mouse IgM was obtained from CALTAG (South San Francisco, CA). Fas-Fc and
TNFR-Fc fusion proteins were gifts from Dr. D. Lynch (Immunex,
Seattle, WA). The pigeon cytochrome C peptide (amino acid residues 88-104: KAERADLIAYLKQATAK) was synthesized by
the Peptide Synthesis Facility (National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, MD).
)2
goat anti-mouse IgM (data not shown). The cells (106 cells/ml)
were resuspended in RPMI 1640 medium with 10% FCS, 0.2 mM glutamine, 5 × 10
4 M
-mercaptoethanol (RPMI complete medium) containing 100 µg/ml LPS, or 5 µg/ml anti-CD40 and cultured at 37°C for 2 or 3 d before use.
Fas-dependent and Antigen-specific Lysis of B Cells by CD4+
T Cells.
Fig. 1.
Lysis of B cells by
CD4+ T cells. (A) Freshly isolated resting B cells, and LPS- or
anti-CD40-activated B cells derived from B10.A mice were labeled with 51Cr and pulsed with
antigen. A.E7 cells were mixed
with the labeled B cells for a 4 h
51Cr-release assay. (B) B cells derived from B10.A mice were
stimulated with LPS and labeled
with 51Cr. A.E7 cells were mixed
with the labeled B cells for a 4 h
51Cr-release assay in the absence
or presence of 10 µg/ml anti-CD4, anti-CD8, Fas-Fc, or
TNFR-Fc. (C) Freshly isolated
resting B cells, LPS- or anti-CD40-activated B cells derived
from C57BL/6 mice were labeled with 51Cr. CD4+ allo-reactive CTL were mixed with the labeled B cells for a 4 h 51Cr-release
assay. (D) B cells derived from
C57BL/6 mice were stimulated with LPS and labeled with 51Cr.
MLR-derived CD4+ CTLs
were mixed with the labeled B
cells for a 4 h 51Cr-release assay
in the absence or presence of 10 µg/ml anti-CD4, anti-CD8,
Fas-Fc, or TNFR-Fc. The results are representatives of three
experiments and the results were
shown as average of triplicates
with standard deviation.
[View Larger Version of this Image (32K GIF file)]
Fig. 2.
Inhibition of CD4+ T cell-dependent lysis of B cells. (A) B
cells derived from B10.A mice were stimulated with LPS and labeled with
51Cr and pulsed with antigen. A.E7 cells were mixed with the labeled B
cells for a 4 h 51Cr-release assay in the absence or presence of 10 µg/ml
mAbs or control rat or hamster IgG. (B) B cells derived from C57BL/6
mice were stimulated with LPS and labeled with 51Cr. MLR-derived
CD4+ CTLs were mixed with the labeled B cells for a 4 h 51Cr-release
assay in the absence or presence of 10 µg/ml mAbs or control rat or hamster IgG. (C) LPS blasts prepared from C57BL/6 mice were resuspended
in RPMI complete medium (106 cells/ml) containing 1 µg/ml either
control hamster IgG or Jo2 antibody. The cells were added to 96-well
plates (200 µl/well) and 10 µg/ml of various mAbs or control rat or hamster IgG were added to the cultures as indicated. After culture at 37°C for 18 h, the cells were harvested and the recovery of viable cells and the percentage of cell loss was calculated. The results presented are representatives of two experiments and the results were presented as average of triplicates with standard deviation.
[View Larger Version of this Image (38K GIF file)]
Fig. 3.
Suppression of activated AE.7-mediated lysis of B cells. AE.7
cells without (A) or with (C) further stimulation by B10A spleen cells plus
antigen for 6 h were purified by Ficoll gradient separation. The AE.7 cells
were then mixed with 51Cr-labeled B10A B cells pulsed with antigen for
a 4 h 51Cr-release assay. For FasL staining, AE.7 cells were cultured in RPMI
complete medium containing 10 µg/ml KBR8301 without (B) or with
(D) the stimulation by B10A spleen cells plus antigen and were purified
by Ficoll gradient separation. The cells were either stained with FITC-conjugated anti-CD4 with (solid line) or without (dotted line) PE-conjugated anti-FasL, and analyzed by flow cytometry. Live CD4+ AE.7 cells
were gated for analysis. The results are representatives of two experiments.
[View Larger Version of this Image (27K GIF file)]
Fig. 4.
Staining of Fas,
LFA-1, ICAM-1, and ICAM-2
on B cells. Freshly purified B
cells and LPS- or anti-CD40-
stimulated B cells were stained
with 1 µg/ml PE-conjugated
anti-Fas, FITC-conjugated anti-
LFA-1, PE-conjugated anti-
ICAM-1, or PE-conjugated
anti-ICAM-2. Isotype-matched
FITC- or PE-conjugated rat
anti-CD4 or PE-conjugated hamster anti-CD3 was used as
negative controls (dotted line). The results presented are representatives of four experiments.
[View Larger Version of this Image (27K GIF file)]
/
B cells express similar levels of Fas (data not
shown). However, LPS- or anti-CD40-stimulated B cells
from ICAM-1
/
mice are not efficiently lysed (Fig. 5).
These data support the concept that it is LFA-1 on Th1
cells and ICAM-1 on B cells that are crucial for apoptosis.
However, the deficiency of ICAM-1 on B cells did not
completely block killing. This raised the possibility that
ICAM-2 (22) could promote T-B adhesion in the absence
of ICAM-1. Alternatively, the residual killing of ICAM-1
/
B cells could result from the binding of LFA-1 on B
cells to ICAM-1 on T cells. Additional assays with ICAM-1-deficient B cells enabled us to examine these possibilities.
The addition of anti-ICAM-1 did not further reduce the
killing of ICAM-1
/
B cells (Fig. 6). By contrast, anti-
ICAM-2 alone completely blocked B cell lysis. This argues
that the interaction of LFA-1 on the B cells with ICAM-1
on the Th1 cells does not play a significant role in T-B cell
interactions. Rather ICAM-1, and to some degree ICAM-2, on B cells interacting with LFA-1 on T cells appear to be
crucial for Fas-mediated B cell killing. Why the interaction of LFA-1 on B cells and ICAM-1 on T cells is not required
is unclear, although flow cytometry reveals their abundant
expression. Interestingly, it has been shown that LFA-1
binding on T cells is transiently activated by TCR stimulation (23). It is possible that TCR engagement during T-B
synapsis transiently upregulates LFA-1 adhesivity on T cells
but LFA-1 on B cells remains inactive.
Fig. 5.
Resistance to CD4+ T cell-mediated lysis by B cells from
ICAM-1/
mice. Freshly isolated resting B cells and LPS- or anti-CD40-activated B cells derived from 8-wk-old C57BL/6 ICAM-1+/+ or
C57BL/6 ICAM-1
/
mice were labeled with 51Cr. MLR-derived
CD4+ CTLs were mixed with the labeled B cells for a 4 h 51Cr-release
assay. The results are representatives of three experiments and were
shown as average of triplicates with standard deviation.
[View Larger Version of this Image (13K GIF file)]
Fig. 6.
Inhibition of CD4+
CTL-mediated lysis of B cells
from C57BL/6 ICAM-1/
mice by anti-ICAM-2. B cells
derived from C57BL/6 ICAM-1+/+ or ICAM-1
/
mice were
stimulated with LPS and labeled
with 51Cr. MLR-derived CD4+
CTLs were mixed with the labeled B cells for a 4 h 51Cr-release assay in the absence or
presence of 5 µg/ml mAbs or control rat or hamster IgG. The
results are representatives of two
experiments and were shown as
the average of triplicates with standard deviation.
[View Larger Version of this Image (21K GIF file)]
/
mice (references 24 and 25
and data not shown), but a 30% increase in IgM+ B cells
was consistently observed in the spleens of ICAM-1
/
mice at 6 mo of age as compared with wild type mice (data
not shown). This suggests that B cells accumulate in these
mice with aging. This could be analogous to lpr mice
which gradually develop abnormal B cell accumulation and
autoimmunity depending on the background of the mouse
strain (26). Although difficult to verify experimentally, our
result is consistent with the hypothesis that ICAM-1 is important for B cell apoptosis mediated by T cells in vivo.
However, no significant production of autoantibodies has yet been observed in older ICAM-1
/
mice (data not
shown). This could be because autoreactive T cells have
not accumulated in these mice since T cell apoptosis is not affected by ICAM-1 deficiency (data not shown). An alternative explanation is that the ICAM-1
/
mice used here
are on C57BL/6 background which is not prone to autoimmunity. ICAM-1 deficiency on autoimmune mouse
backgrounds, such as the MRL strain, might be more appropriate to address such questions.
Address correspondence to Michael J. Lenardo, Laboratory of Immunology, NIAID, NIH, Bldg 10, RM 11D09, 10 Center Drive MSC 1892, Bethesda, MD 20892-1892. Phone: 301-496-6754; FAX: 301-496-0222; E-mail: lenardo{at}nih.gov
Received for publication 18 June 1997 and in revised form 31 July 1997.
J. Wang was supported by a Fellowship from the Arthritis Foundation.We thank Dr. H. Kojima for technical support, Dr. J. Erikson for measuring autoantibodies, Drs. D. Lynch and H. Yagita for reagents, Dr. J. Puck for generous support and encouragement, and Drs. R. Germain, E. Dudley, L. D'Adamio, L. Zheng, and R. Siegel for critical reading of the manuscript.
1. | Ju, S.T., H. Cui, D.J. Panka, R. Ettinger, and A. Marshak-Rothstein. 1994. Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells. Proc. Natl. Acad. Sci. USA. 91: 4185-4189 [Abstract]. |
2. | Rothstein, T.L., J.K. Wang, D.J. Panka, L.C. Foote, Z. Wang, B. Stanger, H. Cui, S.T. Ju, and A. Marshak-Rothstein. 1995. Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells. Nature (Lond.). 374: 163-165 [Medline]. |
3. | Nagata, S., and P. Golstein. 1995. The Fas death factor. Science (Wash. DC). 267: 1449-1456 [Medline]. |
4. | Krammer, P.H., I. Behrmann, P. Daniel, J. Dhein, and K.M. Debatin. 1994. Regulation of apoptosis in the immune system. Curr. Opin. Immunol. 6: 279-289 [Medline]. |
5. | Nagata, S., and T. Suda. 1995. Fas and Fas ligand: lpr and gld mutations. Immunol. Today. 16: 39-43 [Medline]. |
6. | Fisher, G.H., F.J. Rosenberg, S.E. Straus, J.K. Dale, L.A. Middleton, A.Y. Lin, W. Strober, M.J. Lenardo, and J.M. Puck. 1995. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 81: 935-946 [Medline]. |
7. | Rieux-Laucat, F., F. Le Deist, C. Hivroz, I.A. Roberts, K.M. Debatin, A. Fischer, and J.P. de Villartay. 1995. Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science (Wash. DC). 268: 1347-1349 [Medline]. |
8. |
Sneller, M.C.,
J. Wang,
J.K. Dale,
W. Strober,
L.A. Middelton,
Y. Choi,
T.A. Fleisher,
M.S. Lim,
E.S. Jaffe,
J.M. Puck, et al
.
1997.
Clinical, immunologic, and genetic features of an
autoimmune lymphoproliferative syndrome associated with
abnormal lymphocyte apoptosis.
Blood.
89:
1341-1348
|
9. | Scott, D.W., T. Grdina, and Y. Shi. 1996. T cells commit suicide, but B cells are murdered! J. Immunol. 156: 2352-2356 [Abstract]. |
10. | Onel, K.B., C.L. Tucek-Szabo, D. Ashany, E. Lacy, J. Nikolic-Zugic, and K.B. Elkon. 1995. Expression and function of the murine CD95/FasR/APO-1 receptor in relation to B cell ontogeny. Eur. J. Immunol. 25: 2940-2947 [Medline]. |
11. | Rathmell, J.C., M.P. Cooke, W.Y. Ho, J. Grein, S.E. Townsend, M.M. Davis, and C.C. Goodnow. 1995. CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature (Lond.). 376: 181-184 [Medline]. |
12. | Rathmell, J.C., S.E. Townsend, J.C. Xu, R.A. Flavell, and C.C. Goodnow. 1996. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell. 87: 319-329 [Medline]. |
13. |
Daniel, P.T., and
P.H. Krammer.
1994.
Activation induces
sensitivity toward APO-1 (CD95)-mediated apoptosis in human B cells.
J. Immunol.
152:
5624-5632
|
14. | Garrone, P., E.M. Neidhardt, E. Garcia, L. Galibert, C. van Kooten, and J. Banchereau. 1995. Fas ligation induces apoptosis of CD40-activated human B lymphocytes. J. Exp. Med. 182: 1265-1273 [Abstract]. |
15. | Schattner, E.J., K.B. Elkon, D.H. Yoo, J. Tumang, P.H. Krammer, M.K. Crow, and S.M. Friedman. 1995. CD40 ligation induces Apo-1/Fas expression on human B lymphocytes and facilitates apoptosis through the Apo-1/Fas pathway. J. Exp. Med. 182: 1557-1565 [Abstract]. |
16. | Lynch, D.H., F. Ramsdell, and M.R. Alderson. 1995. Fas and FasL in the homeostatic regulation of immune responses. Immunol. Today. 16: 569-574 [Medline]. |
17. | Boehme, S.A., and M.J. Lenardo. 1993. Propriocidal apoptosis of mature T lymphocytes occurs at S phase of the cell cycle. Eur. J. Immunol. 23: 1552-1560 [Medline]. |
18. | Kayagaki, N., A. Kawasaki, T. Ebata, H. Ohmoto, S. Ikeda, S. Inoue, K. Yoshino, K. Okumura, and H. Yagita. 1995. Metalloproteinase-mediated release of human Fas ligand. J. Exp. Med. 182: 1777-1783 [Abstract]. |
19. |
Hecht, T.T.,
D.L. Longo, and
L.A. Matis.
1983.
The relationship between immune interferon production and proliferation in antigen-specific, MHC-restricted T cell lines and
clones.
J. Immunol.
131:
1049-1055
|
20. | Kato, K., M. Koyanagi, H. Okada, T. Takanashi, Y.W. Wong, A.F. Williams, K. Okumura, and H. Yagita. 1992. CD48 is a counter-receptor for mouse CD2 and is involved in T cell activation. J. Exp. Med. 176: 1241-1249 [Abstract]. |
21. |
Medema, J.P.,
C. Scaffidi,
F.C. Kischkel,
A. Shevchenko,
M. Mann,
P.H. Krammer, and
E. Peter.
1997.
FLICE is activated
by association with the CD95 death-inducing signaling complex (DISC).
EMBO (Eur. Mol. Biol. Organ.) J.
16:
2794-2804
|
22. | de Fougerolles, A.R., and T.A. Springer. 1992. Intercellular adhesion molecule 3, a third adhesion counter-receptor for lymphocyte function-associated molecule 1 on resting lymphocytes. J. Exp. Med. 175: 185-190 [Abstract]. |
23. | Dustin, M.L., and T.A. Springer. 1989. T-cell receptor cross-linking transiently stimulates adhesiveness through LFA-1. Nature (Lond.). 341: 619-624 [Medline]. |
24. |
Sligh, J.E. Jr.,
C.M. Ballantyne,
S. Rich,
H.K. Hawkins,
C.W. Smith,
A. Bradley, and
A.L. Beaudet.
1993.
Inflammatory and immune responses are impaired in mice deficient in
intercellular adhesion molecules 1.
Proc. Natl. Acad. Sci. USA.
90:
8529-8533
|
25. | Xu, H., J.A. Gonzalo, Y. St. Pierre, I.R. Williams, T.S. Kupper, R.S. Cotran, T.A. Springer, and J.C. Gutierrez-Ramos. 1994. Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J. Exp. Med. 180: 95-109 [Abstract]. |
26. | Cohen, P.L., E. Creech, D. Nakul-Aquaronne, R. McDaniel, S. Ackler, R.G. Rapoport, E.S. Sobel, and R.A. Eisenberg. 1993. Antigen nonspecific effect of major histocompatibility complex haplotype on autoantibody levels in systemic lupus erythematosus-prone lpr mice. J. Clin. Invest. 91: 2761-2768 [Medline]. |