| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
TNF, the prototype member of this family, is also potentially important
in the induction of programmed cell death (1). This
cytokine is a product of many cell types, but particularly of
leukocytes, and is an important mediator in the early stages of the
inflammatory response (1). Experiments with gene knockout
mice have also shown that the two TNFRs, TNFR1 (p55) (6)
and TNFR2 (p75) (7), participate in the induction of
apoptosis and subsequent deletion of Ag-specific mature T cells.
However, p55-/- and
p75-/- mice are normal with respect to size and
the composition of their lymphocyte compartments (8, 9).
Both Fas and TNFR1 contain conserved death domains in their cytoplasmic
tails, which mediate defined protein-protein interactions (10, 11), allowing the recruitment of other death domain-containing
proteins such as Fas-associated death domain protein (FADD) (MORT1),
TNFR-associated death domain protein, or receptor interacting protein
(RIP) (12, 13, 14, 15, 16, 17). The association of FADD to Fas or TNFR1
results in the recruitment of Fas-associated death domain-like
IL-1-converting enzyme/MORT1-associated CED-3 homologue (caspase 8),
the activation of which in turn leads to cell death (18, 19). In contrast to Fas or TNFR1, the cytoplasmic tail of TNFR2
does not contain a death domain and does not interact with death
domain-containing proteins such as FADD, RIP, or TNFR-associated death
domain protein. However, several studies have shown that TNFR2 can also
transduce TNF-dependent apoptotic signals (7, 20). More
recently, it was shown that cell death mediated by TNFR2 is dependent
on the presence of RIP, a protein Ser/Thr kinase previously shown to be
required for NF-
B activation by TNFR1 (21). These
studies suggest that other signaling molecules mediate the induction of
cell death by this receptor. The cytoplasmic tail of TNFR2 has been
shown to interact with signal transduction molecules known as
TNFR-associated factor (TRAF) proteins, particularly TRAF1 and TRAF2
(22). In some cases, the TRAF proteins have been shown to
mediate various biological effects exerted by their cognate receptors.
For example, TRAF2 was shown to mediate NF-B activation
(23, 24, 25).
In this study, we have used Con A-activated CD4 and CD8 T cells from lpr/lpr, TNFR1-/-, or TNFR2-/- mice to determine the relative contribution of the TNF and Fas signaling pathways in inducing cell death in these cells. Our findings are consistent with the hypothesis that TNFR2 plays distinct regulatory roles in cell death induced by TNF or FasL in activated CD4 and CD8 T cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Breeders for C57BL/6 (B6), B6-p55-/-, B6-p75-/-, and B6-lpr/lpr mice were obtained from The Jackson Laboratory (Bar Harbor, ME). These mice were bred at the Animal Unit in our department. Mice of 6–8 wk of age were used for the experiments described.
Abs and flow cytometry
Abs and their specificities were as follows: Jo2, Fas (CD95)
(PharMingen, San Diego, CA); K10, Fas ligand (PharMingen); 53.67,
CD8
(American Type Culture Collection (ATCC), Manassas, VA); 53.58,
CD8ß (ATCC); GK1.5, CD4 (ATCC); 145-2C11, CD3
(ATCC); 55R-593, p55
(Genzyme, Cambridge, MA); TR75-32, p75 (Genzyme). A FACScan equipped
with the LYSYS II software (Becton Dickinson) was used to acquire and
analyze the data. For three-color analysis, a total of 25,000 events
was acquired.
Cell cultures
CD4+CD8- (CD4) and CD4-CD8+ (CD8) T cells were isolated from the lymph nodes of the indicated mouse lines by incubating the cells with biotinylated anti-CD4 or anti-CD8ß mAb, respectively, followed by positive selection using a MACS MS+ Separation Column and MiniMACS magnet following the procedure provided by the manufacturer (Miltenyi Biotech, Auburn, CA). The purified CD4 or CD8 lymph node cells were of >95% purity, and 5 x 105/ml of purified cells were cultured with 2.5 µg/ml of Con A and 20 U/ml of IL-2 for 48 h. All cells were cultured in Iscove’s DMEM (Life Technologies, Burlington, Ontario, Canada) supplemented with 10% (v/v) FBS and antibiotics (I-medium). The cultures were then split 1 in 2 in I-medium containing 20 U/ml of IL-2 and cultured for an additional 24 h. After this culture period, the cells were assessed for the expression of cell surface markers or in TCR-induced cell death assays, as indicated. For assessment of TCR-induced cell death, day 3 activated cells (1 x 105) were plated onto flat-bottom microtiter wells that had been precoated with 1 µg/ml of 2C11 mAb in 0.20 ml of I-medium containing 20 U/ml of IL-2. After an incubation period of 16 h, the cells were collected from individual wells and assessed for cell death. This was done by incubating the cells with 7-amino actinomycin D (7-AAD; Calbiochem, La Jolla, CA), as previously described (26, 27). The cells were then fixed with paraformaldehyde and analyzed by FACS. Cells staining 7-AAD- were considered nonapoptotic and viable. The percentage of specific kill was determined as 100 x (1 - (% of viable cells cultured with 2C11)/(% of viable cells that were cultured without 2C11)).
Lysis of Fas-expressing T cells by FasL+ fibroblasts
The 3T3 fibroblasts that have been mock transfected (3T3-PSR
)
or Fas ligand transfected (FasL-3T3) were kindly provided by Dr. Nick
Crispe (Yale University, New Haven, CT). Expression of FasL by the
3T3-PSR and the FasL-3T3 cell lines was determined by FACS analysis.
For assessment of Fas/FasL-mediated killing, day 3 CD4 or CD8 Con A
blasts from various mouse lines were 51Cr
labeled. A total of 1 x 104 51Cr-labeled
cells was plated onto wells containing either 3 x
104, l x 104, or
3 x 103 3T3-PSR or FasL-3T3 cells and
incubated for 6 h at 37°C. Spontaneous release was determined by
incubating 51Cr-labeled Con A blasts for the same
time period in the absence of fibroblasts. Percentage of specific kill
was determined as 100 x ((counts released with fibroblasts
- spontaneous release)/(maximum release - spontaneous release)).
Maximum release was determined by freezing and thawing the
51Cr-labeled Con A blasts three times and
determining the radioactivity released into the culture
supernatant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Cross-linking of the TCR on activated T cells leads to programmed
cell death. This form of programmed cell death is referred to as
propiocidal apoptosis and is dependent on culturing the activated T
cells in IL-2 (28, 29). Propiocidal apoptosis is dependent
at least in part on the expression of Fas on the activated T cells
(30). To determine whether p55 and p75 play any role in
propiocidal apoptosis, we activated purified CD4 and CD8 lymph node T
cells from B6, B6-lpr/lpr,
B6-p55-/-, and
B6-p75-/- mice with Con A and IL-2. Propiocidal
apoptosis was induced by TCR cross-linking. The 7-AAD assay (see
Materials and Methods) was used for distinguishing live from
dead cells. The results in Fig. 1
A indicate that Con
A-activated CD4 T cells from B6 and B6-p75-/-
mice were highly susceptible to propiocidal apoptosis. As expected,
activated CD4 T cells from B6-lpr/lpr mice were relatively
resistant to propiocidal apoptosis (Fig. 1A). Activated CD8
T cells from B6 and B6-lpr/lpr mice were similar to CD4 T
cells in their susceptibility and resistance to propiocidal apoptosis,
respectively (Fig. 1B). Unexpectedly, activated CD8 T cells
from B6-p75-/- mice were highly resistant to
propiocidal apoptosis (Fig. 1B). These results are also
expressed as percentage of specific kill (Fig. 1C) because
this form of data presentation offers a more quantitative way for
comparing results between the various groups. We also found that
similar to cells from B6 mice, activated CD4 and CD8 T cells from
B6-p55-/- mice were also highly susceptible to
propiocidal apoptosis (Fig. 1C). Therefore, only the
p75-/-, and not the
p55-/- mutation confers resistance of activated
CD8 T cells to propiocidal apoptosis.
|
indicate that Fas
expression in Con A-activated CD4 and CD8 T cells is not affected by
the p75-/- mutation. Similarly, the expression
of p75 in Con A-activated CD4 and CD8 T cells is not affected by the
lpr mutation. The fluorescence data also indicate that CD4
and CD8 Con A blasts from B6-lpr/lpr and
B6-p75-/- mice did not express detectable level
of Fas and p75, respectively.
|
Propiocidal apoptosis is also dependent on the induction of FasL
in activated T cells as a result of TCR cross-linking
(31, 32, 33, 34, 35). Therefore, one potential explanation for the
resistance of activated p75-/- CD8 T cells to
propiocidal apoptosis is that these cells do not up-regulate FasL upon
TCR cross-linking. To determine whether activated
p75-/- CD8 T cells can up-regulate FasL as a
result of TCR cross-linking, Con A-activated CD8 T cells from B6,
B6-lpr/lpr, and B6-p75-/- mice were
stimulated with an anti-CD3 mAb for 6 h, and the induction
of FasL expression on these cells was quantitated by flow cytometry.
The 6-h incubation time is insufficient for most cells to undergo
propiocidal apoptosis and offers a suitable time point for assessment
of FasL expression. The results in Fig. 3
indicate that p75-/- CD8 T cells were able to
up-regulate FasL at least as efficiently as B6 CD8 T cells after TCR
stimulation. Thus, the resistance of p75-/- CD8
T cells to propiocidal apoptosis is not due to the inability of these
cells to up-regulate FasL after TCR stimulation. We also noted that
B6-lpr/lpr CD8 T cells were the most efficient in expressing
FasL after TCR stimulation, an observation previously reported by other
investigators (36).
|
A. It is clear from this
figure that FasL expression is only detectable in the transfectant cell
line. The data in Fig. 4B showed that CD4 Con A blasts from
B6 and B6-p75-/- mice were equally susceptible
to killing by the FasL+ cell line. As expected,
CD4 blasts from B6-lpr/lpr mice were resistant to killing by
the FasL+ cell line. By contrast, CD8 blasts from
B6-p75-/- mice were much more resistant than
CD8 blasts from B6 mice to killing by the FasL+
cell line (Fig. 4C). This result suggests that the
resistance of CD8 blasts from B6-p75-/- mice to
propiocidal apoptosis is most likely due to the resistance of this cell
population to Fas/FasL-mediated killing.
|
Previous studies have suggested that TCR-induced apoptosis in
activated T cells is mediated in part by TNF and killing by TNF is
mediated by the p75 receptor (7). The availability of
B6-p55-/- and B6-p75-/-
mice allows us to determine more directly whether TNF-induced killing
of CD4 and CD8 Con A blasts is mediated by either the p55 and/or p75
receptor. The sensitivity of CD4 and CD8 Con A blasts to killing by TNF
was determined by culturing these blasts with various concentrations of
TNF in the presence or absence of a low concentration (1 µg/ml) of
the protein synthesis inhibitor, cycloheximide. Previous studies have
shown that the addition of cycloheximide is necessary for the apoptotic
effects of TNF (37, 38). We also found that between 0.1
and 10 ng/ml, TNF by itself does not induce apoptosis in either CD4 or
CD8 blasts from these three lines of mice (data not shown). In the
presence of cycloheximide, CD4 or CD8 Con A blasts from B6 mice were
highly sensitive to killing by TNF (Fig. 5). At the concentrations tested, CD4 or
CD8 blasts from p55-/- mice were completely
resistant to killing by TNF plus cycloheximide (Fig. 5). Although CD4
or CD8 blasts from p75-/- mice were susceptible
to killing by TNF plus cycloheximide, the dose-response curve to TNF
differs from that observed for the corresponding blasts from B6 mice.
At the lowest concentration of TNF (0.1 ng/ml), there was no difference
in susceptibility to killing between CD4 and CD8 blasts from B6 or
B6-p75-/- mice. However, at higher
concentrations of TNF (1 and 10 ng/ml), CD4 and CD8 blasts from
p75-/- mice were more resistant than those from
B6 mice to killing by TNF plus cycloheximide. These results indicate
that expression of the p75 receptor is insufficient for TNF-mediated
apoptosis in both CD4 and CD8 blasts. Furthermore, the absence of the
p75 receptor in these blasts renders them less susceptible to killing
at high concentrations of TNF.
|
The results in Fig. 5
suggest that the p75 receptor is incapable
of transducing TNF-mediated death signals in CD4 and CD8 Con A blasts.
Other studies have suggested that the p75 receptor is required for
optimal proliferation of thymocytes and cytotoxic CD8 T cells
(39). To further define the function of the p75 receptor
in CD4 and CD8 T cells, we determined whether the p75 receptor is
required for the optimal proliferative response of CD4 and CD8 T cells
in response to TCR stimulation. This was done by purifying CD4 and CD8
T cells from the lymph nodes of B6 and
B6-p75-/- mice and activating them with an
anti-TCR mAb plus IL-2 and measuring their proliferative response 2
days later. The data in Fig. 6 indicate
that the proliferative responses of purified CD4 and CD8 T cells from
B6-p75-/- mice in response to anti-TCR
stimulation were about 2-fold less than that observed for corresponding
cells from B6 mice. By contrast, the proliferative responses of CD4 and
CD8 T cells from B6-p55-/- mice in response to
stimulation by anti-TCR mAb + IL-2 were similar to that of CD4 or
CD8 T cells from B6 mice (data not shown). Thus, the p75, but not the
p55, receptor is required for optimal proliferative responses of
anti-TCR-stimulated CD4 and CD8 T cells.
|
show that
fairly similar number of CD8 T cells were recovered from
anti-TCR-stimulated during the first 3 days of culture. However, on
day 4, significantly more number of CD8 T cells were recovered from
cultures of p75-/- cells relative to B6
cultures. By contrast, fewer CD4 T cells were recovered from
p75-/- cultures relative to B6 cultures, and
this lower recovery was evident by day 3 after TCR stimulation. The
increase in yield of p75-/- CD8 cells after 4
days of culture was also reflected in the CD8/CD4 ratios of the
cultured cells. Before culture, the CD8/CD4 ratios of spleen cells from
B6 and p75-/- mice were 0.58 and 0.50,
respectively. After 4 days of culture, the CD8/CD4 ratio was 2.3 for B6
and 4.1 for p75-/- spleen cells. These
observations are consistent with our conclusions that the absence of
the p75 receptor confers a survival advantage for CD8, but not CD4, T
cells with regard to TCR-induced cell death.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In the presence of low concentrations of cycloheximide, activated
CD4 and CD8 T cells are killed by TNF (Fig. 5). Under our assay
conditions, TNF-mediated killing of these cells is dependent on two
factors: 1) the presence of the p55 receptor, and 2) the inclusion of
cycloheximide in the killing assay. Zheng et al. (7) have
previously reported that the killing of activated CD8 T cells by TNF is
mediated by the p75 receptor. The authors’ conclusion was based in
part on the failure to detect expression of the p55 receptor on
activated CD4 and CD8 T cells. We have also been unable to detect
expression of the p55 receptor on activated CD4 and CD8 T cells by FACS
analysis (data not shown). However, the abrogation of killing by TNF
plus cycloheximide in activated p55-/- CD4 or
CD8 T cells (Fig. 5) indicates that p55 is essential for this process.
Therefore, p55 must be expressed on these cells at a level that is
below detection by FACS analysis. Our data also indicate that TNF is
unable to induce killing of either activated CD4 or CD8 T cells via the
p75 receptor because activated p55-/- CD4 or
CD8 T cells express the same level of p75 as activated cells from B6
mice (data not shown) and these cells are resistant to killing by TNF
plus cycloheximide (Fig. 5). Speiser et al. (6) have also
shown that the p55 receptor is required for the deletion of activated
CD8 cytotoxic T cells in vivo. We found that the role of p75 is to
augment TNF-induced, p55-mediated killing at high concentrations of TNF
(Fig. 5). The augmentation of TNF-induced, TNFR1-mediated cell death by
TNFR2 has also been observed by Weiss et al. (37).
Previous studies have shown that TNFR1 can mediate both apoptotic and
antiapoptotic signals (15, 40). Weiss et al.
(37) proposed that the augmentation of TNF/TNFR1-mediated
cell death by TNFR2 may be due to the sequestration of antiapoptotic
proteins by the p75 receptor complex. p75 may also augment
TNF/TNFR1-mediated killing of CD4 and CD8 T cells by a similar
mechanism.
The role of p75 in TCR- and Fas-mediated killing of activated CD4 and CD8 T cells
We found that TCR-mediated killing of activated CD8, but not CD4,
T cells is drastically reduced in the absence of the p75 receptor (Fig. 1). Zheng et al. (7) proposed that there are two effector
mechanisms associated with cell death induced by cross-linking the TCR
on activated T cells. The first is the induction of FasL in activated T
cells as a result of TCR cross-linking, and this can lead to activation
of the Fas death pathway as a result of Fas-FasL interaction. The
second mechanism is that TCR stimulation of activated T cells leads to
the production of TNF, which initiates the TNF-dependent death pathway.
Zheng et al. (7) proposed that the Fas/FasL-mediated
pathway is sufficient for TCR-induced killing of activated CD4 T cells.
They also proposed that Fas/FasL-mediated killing of activated CD8 T
cells is a minor pathway, and the major pathway for TCR-induced cell
death of activated CD8 T cells is mediated by a p75-dependent TNF
pathway. Our data are inconsistent with these conclusions for the
following reasons: 1) Activated CD8 T cells lacking the p55 receptor
are not killed by TNF plus cycloheximide (Fig. 5); this observation
suggests that TNF-induced cell death in activated CD8 T cells operates
through the p55 receptor. 2) Activated B6 CD8 T cells, which express
Fas, can be killed very efficiently by FasL+
fibroblasts (Fig. 4). This observation indicates that the
Fas/FasL-mediated death pathway is not defective in activated CD8 T
cells. 3) Activated p55-/- CD8 T cells, which
express the same level of the p75 receptor as activated B6 CD8 T cells,
are not killed by TNF plus cycloheximide (Fig. 5), suggesting that
TNF-dependent death signals are not transmitted through the p75
receptor.
Instead of mediating TNF-induced cell death, we found that the p75
receptor is required for efficient Fas/FasL-mediated killing of
activated CD8 T cells (Fig. 4). Together with the finding that the p75
receptor augments TNF/p55-mediated killing, our data are more
consistent with the following alternative explanations for the
resistance of activated p75-/- CD8 T cells to
TCR-induced cell death: 1) activated p75-/- CD8
T cells are highly resistant to Fas/FasL-mediated killing, and 2) the
reduced sensitivity of these cells to TNF/p55-mediated killing.
What are the potential explanations for the relative resistance of
activated p75-/- CD8 T cells to
Fas/FasL-mediated death pathway? Previous studies have shown that
Fas-mediated killing as a result of TCR stimulation is dependent on the
induction of FasL expression after TCR stimulation
(31, 32, 33). However, we found that FasL induction is not
defective in TCR-stimulated p75-/- CD8 T cells
(Fig. 3). Mature T cells have been shown to express high levels of
Fas-associated death domain-like IL-1-converting enzyme-inhibitory
proteins (FLIPs) that block death receptor-induced cell death
(41). Significantly, T cells down-regulate FLIP when they
are activated in vitro, and this down-regulation correlated with the
sensitivity of the activated T cells to Fas/FasL-mediated cell death
(42, 43, 44). Retrovirus-mediated expression of cellular FLIP
(c-FLIP) blocks Fas-induced apoptosis of activated T lymphocytes, but
does not affect cell death resulting from cytokine withdrawal
(44). It remains to be determined whether the p75 receptor
complex may recruit and sequester c-FLIP away from the Fas receptor
complex and in this way interferes with Fas/FasL-mediated killing. The
p75 receptor complex can also recruit cellular inhibitors of apoptosis
proteins (c-IAPs) (45), which contribute to antiapoptotic
signals (46, 47). Therefore, another potential mechanism
for the regulation of Ag-induced cell death by the p75 receptor is
through the sequestration of proteins such as c-IAPs away from the Fas
receptor complex.
It is interesting to note that Fas/FasL-mediated killing of activated CD4 T cells is not regulated by the p75 receptor. A potential explanation for the independence on the p75 receptor of activated CD4 T cells to Fas-mediated killing is that inhibitors of Fas-mediated killing such as c-FLIP and/or c-IAPs may be present at relatively low levels in activated p75-/- CD4 T cells, and the sequestration of these factors by the p75 receptor complex may not be required for Fas-mediated killing of activated CD4 T cells. This possibility is being investigated.
The lpr and gld phenotypes are affected by p55-/- and TNF-/- mutations
The lpr phenotype is accelerated in
p55-/- lpr/lpr mice
(48). More recently, it was shown that
TNF-/- gld/gld mice have a much less
severe gld phenotype (49). The
lymphoproliferative disorder in lpr and the gld
mice is due to the accumulation of the
CD4-CD8-ß
TCR+ B220+
(double-negative) T cell population in the peripheral lymphoid organs
of these mice (5). It is conceivable that in
p55-/- lpr/lpr mice, there is a lack
of signaling through p55, but signaling through the p75 receptor can
still occur. We speculate that signaling through the p75 receptor may
promote the proliferation of double-negative cells and exacerbates the
lpr phenotype. The requirement for the p75 receptor for
optimal proliferative responses is most likely due to the activation of
NF-B-mediated signaling pathways (23, 24), which has
been shown to antagonize TNF-mediated apoptosis (50, 51, 52).
By contrast, in TNF-/- gld/gld mice,
signaling through the p75 receptor cannot occur and proliferative
signals offered by the p75 receptor are lacking for these cells, and
this may account for the less severe gld phenotype.
The studies in the lpr and gld mice and our present work illustrate that Fas and TNF signaling pathways are intimately related. We have demonstrated that signaling through TNFR1 and the Fas receptor can be regulated by TNFR2 signals. Delineation of the nature of the cross-talk between distinct receptors of the TNFR family will undoubtedly lead to novel insights regarding the multiple functions of these receptors and the molecular basis for the multifaceted manifestations of the lymphoproliferative and autoimmune disorders associated with the gld and lpr mutations.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Hung-Sia Teh, Department of Microbiology and Immunology, University of British Columbia, 6174 University Boulevard, Vancouver, British Columbia, Canada V6M 2M5.
3 Abbreviations used in this paper: FasL, Fas ligand; 7-AAD, 7-amino actinomycin D; FLIP, Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein; c-FLIP, cellular FLIP; c-IAP, cellular inhibitor of apoptosis protein; FADD, Fas-associated death domain protein; RIP, receptor interacting protein; TRAF, TNFR-associated factor.
Received for publication May 3, 2000. Accepted for publication July 31, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
B activation. Cell 81:495.[Medline]
B by TNR receptor 2 and CD40. Science 269:1424.B activation. Genes Dev. 10:963.B activation and binding specificity. Proc. Natl. Acad. Sci. USA 93:9699.ß T lymphocytes for apoptosis. Nature 353:858.[Medline]
B activation prevents cell death. Cell 87:565.[Medline]
B in preventing TNF-induced death. Science 274:782.-induced apoptosis by NF-B. Science 274:787. and cancer therapy-induced apoptosis: potentiation by inhibition of NF-B. Science 274:784.This article has been cited by other articles:
|
|
 |
|
  C. R. Greenfeld, K. F. Roby, M. E. Pepling, J. K. Babus, P. F. Terranova, and J. A. Flaws Tumor Necrosis Factor (TNF) Receptor Type 2 Is an Important Mediator of TNF alpha Function in the Mouse Ovary Biol Reprod, February 1, 2007; 76(2): 224 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. Frankel, G. P. Cosgrove, S.-I. Cha, C. D. Cool, M. W. Wynes, B. L. Edelman, K. K. Brown, and D. W. H. Riches TNF-{alpha} Sensitizes Normal and Fibrotic Human Lung Fibroblasts to Fas-Induced Apoptosis Am. J. Respir. Cell Mol. Biol., March 1, 2006; 34(3): 293 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Chen, Z. Tong, Q. Ye, S. Nakamura, U. Costabel, and J. Guzman Expression of tumour necrosis factor receptors by bronchoalveolar cells in hypersensitivity pneumonitis Eur. Respir. J., June 1, 2005; 25(6): 1039 - 1043. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Till, P. Rosenstiel, A. Krippner-Heidenreich, S. Mascheretti-Croucher, P. J. P. Croucher, H. Schafer, P. Scheurich, D. Seegert, and S. Schreiber The Met-196 -> Arg Variation of Human Tumor Necrosis Factor Receptor 2 (TNFR2) Affects TNF-{alpha}-induced Apoptosis by Impaired NF-{kappa}B Signaling and Target Gene Expression J. Biol. Chem., February 18, 2005; 280(7): 5994 - 6004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Murray and I. N. Crispe TNF-{alpha} Controls Intrahepatic T Cell Apoptosis and Peripheral T Cell Numbers J. Immunol., August 15, 2004; 173(4): 2402 - 2409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Malewicz, N. Zeller, Z. B. Yilmaz, and F. Weih NF{kappa}B Controls the Balance between Fas and Tumor Necrosis Factor Cell Death Pathways during T Cell Receptor-induced Apoptosis Via the Expression of Its Target Gene A20 J. Biol. Chem., August 29, 2003; 278(35): 32825 - 32833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Lee, Y. Park, J. K. Yoo, S. Y. Choi, and Y. C. Sung Inhibition of TCR-Induced CD8 T Cell Death by IL-12: Regulation of Fas Ligand and Cellular FLIP Expression and Caspase Activation by IL-12 J. Immunol., March 1, 2003; 170(5): 2456 - 2460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. F. Davidson, C. Haudenschild, J. Kwon, and M. S. Williams T Cell Receptor Ligation Triggers Novel Nonapoptotic Cell Death Pathways That Are Fas-Independent or Fas-Dependent J. Immunol., December 1, 2002; 169(11): 6218 - 6230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Tham and M. F. Mescher The Poststimulation Program of CD4 Versus CD8 T Cells (Death Versus Activation-Induced Nonresponsiveness) J. Immunol., August 15, 2002; 169(4): 1822 - 1828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Zapata and J. C. Reed TRAF1: Lord Without A RING Sci. Signal., May 21, 2002; 2002(133): pe27 - pe27. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Y. Kim and H.-S. Teh TNF Type 2 Receptor (p75) Lowers the Threshold of T Cell Activation J. Immunol., December 15, 2001; 167(12): 6812 - 6820. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Elzey, T. S. Griffith, J. M. Herndon, R. Barreiro, J. Tschopp, and T. A. Ferguson Regulation of Fas Ligand-Induced Apoptosis by TNF J. Immunol., September 15, 2001; 167(6): 3049 - 3056. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||
