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Immunology Research Division, Department of Pathology, Brigham & Women’s Hospital and Harvard Medical School, Boston, Ma 02115
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The functional roles of Fas and Bcl proteins in the immune system have been examined in a variety of experimental models, including cell lines, as well as transgenic and mutant mice (e. g., 9–13). The results of such studies support the idea that the Fas/FasL pathway is critically involved in the elimination of mature, self-reactive lymphocytes, and Bcl proteins are important for lymphocyte survival in response to growth factors and various activating stimuli (reviewed in 14). However, whether these pathways serve distinct or overlapping functions is an issue of considerable uncertainty. Importantly, little has been done to explore the functions of these pro- and antiapoptotic proteins in the physiologic responses of homogeneous lymphocyte populations specific for defined Ags. To address this issue, we have bred a TCR transgene into lpr mice, which lack functional Fas (5, 6), and into mice that constitutively express Bcl-2 in T cells (11). We have analyzed the responses of these T cells to their cognate Ag in vivo, and to the Ag expressed as a "self" protein in transgenic mice. Our results support the hypothesis that Fas and Bcl-2 regulate pathways of apoptosis that are largely distinct and serve different physiologic functions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All mice used were 6 to 10 wk old and were maintained in accordance with the guidelines of the Committee on Animals of Harvard Medical School and those prepared by the Committee of Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. Mice expressing the transgenic 3A9 TCR, specific for HEL46–61 + I-Ak (15), were kindly provided by Dr. M. Davis (Stanford University, Palo Alto, California). The 3A9 transgene was expressed on a B10.BR (H-2k) background. MRL-lpr/lpr mice were obtained from The Jackson Laboratory, Bar Harbor, Maine. To generate TCR transgenic mice that lacked functional Fas, 3A9 TCR transgenic mice were backcrossed with MRLlpr/lpr mice for four to six generations. Mice expressing human Bcl-2 under the control of the EµPµ promoter element were also obtained from The Jackson Laboratory. This strain of Bcl-2 transgenic mice constitutively expresses human Bcl-2 in all immature and mature T cells (11), on a C57BL/6J (H-2b) background. To generate TCR transgenic mice that carry a Bcl-2 transgene, 3A9 TCR transgenic mice (H-2k) were initially crossed directly with the commercially available Bcl-2 transgenic mice (H-2b). It was discovered that the T cells bearing the 3A9 TCR transgene do not mature normally in mice that are heterozygous (H-2k/b) at the MHC locus, and CD4+ T cells derived from 3A9 (H-2k/b) mice respond poorly to HEL46–61 peptide (L.V.P., unpublished data). Therefore, the Bcl-2 transgene was first backcrossed onto an H-2k background (B10.BR) for two generations, until H-2k homozygous Bcl-2 transgenic mice were available to mate with 3A9 TCR transgenic mice. 3A9 mice that expressed the lpr mutation (3A9/lpr) or the Bcl-2 transgene (3A9/Bcl-2), or were wild-type at both loci (3A9/+), and all homozygous for the H-2k haplotype were used in the experiments presented here.
To generate TCR transgenic mice that also expressed a "self" Ag, 3A9 TCR transgenic mice were crossed with mice that expressed high serum concentrations (approximately 20 ng/ml) of soluble4 hen egg white lysozyme (sHEL, ref. 16). sHEL transgenic mice were kindly provided by Dr. C. Goodnow (John Curtin School of Medicine, Canberra, Australia). Since the sHEL transgene was expressed on a C57BL/6 (H-2b) background, sHEL mice were first backcrossed four generations with MRL +/+ or MRL-lpr/lpr mice, to generate mice that were homozygous for H-2k, and either wildtype (sHEL/+) or Fas-mutant (sHEL/lpr). To generate TCR transgenic mice expressing a "self" Ag, which lacked functional Fas or expressed a Bcl-2 transgene, 3A9/lpr mice were bred with sHEL/lpr mice, and 3A9/Bcl-2 mice were bred with sHEL/+ mice. H-2k homozygous 3A9 mice that expressed both HEL and mutant Fas (3A9 x HEL/lpr), or a Bcl-2 transgene (3A9 x HEL/Bcl-2), or control mice (3A9 x HEL/+) were used in the experiments presented here.
Genotyping TCR transgenic mice
The genotype of all mice used here was determined by PCR analysis of tail DNA. The following PCR primers were used to identify the various transgenes and mutant genes studied: 3A9 (15), 5' GCA GTC ACC CAA AGC CCA AG 3' and 5' CCC CAG CTC ACC TAA CAC TG 3', yielding a PCR product of 371 bp; lpr (13), 5' GTA AAT AAT TGT GCT TCG TCA G 3' and 5' TAG AAA GCT GCA CGG GTG TG 3', yielding PCR fragments of 212bp (lpr) and 184bp (wildtype); Bcl-2 (17), 5' GCA ACT GAT GAA TGG GAG CAG TGG 3' and 5' GCA GAC ACT CTA TGC CTG TGT GG 3', yielding a PCR fragment of 381 bp; sHEL (18), 5' GAG CGT GAA CTG CGC GAA GA 3' and 5' TCG GTA CCC TTG CAG CGG TT 5', yielding a PCR product of 160 bp; I-Ak/b (19), 5' CAT GGG CAT AGA AAG GGC AGT CTT TGA ACT 3', 5' CAT AGC CCC AAA TGT CTG ACC TCT GGA GAG 3', and 5'AGT CTT CCC AGC CTT CAC ACT CAG AGG TAC 3', yielding PCR products of 155 bp (I-Ab), as well as 210 bp and 780 bp (I-Ak).
Phenotypic analysis of TCR transgenic mice
The numbers of lymphocytes of various types present in the 3A9 mice were calculated by multiplying the total number of viable cells found in lymphoid organs by the percentage of the total cells that each lymphocyte population represented in that organ. The frequency and phenotype of lymphocytes in 3A9 mice were determined by staining an aliquot of 106 viable cells. The mAbs used were FITC-conjugated anti-Vß8 and anti-CD3; phycoerythrin (PE)-conjugated anti-CD4, anti-CD8, and anti-B220; and Cy-Chrome C (CyC)-conjugated anti-CD4 (all from PharMingen, San Diego, California). Analyses were performed on a FACScan flow cytometer (Becton Dickson, San Francisco, California).
In vitro cell death assays
To assay the induction of apoptotic cell death induced by growth factor withdrawal, naive CD4+ T cells, purified using CD4 Dynabeads (Dynal A. S., Oslo, Norway) were cultured in 1 ml of RPMI 1640 supplemented with 1 mM L-glutamine, penicillin, streptomycin, nonessential amino acids, sodium pyruvate, and HEPES (all from Life Technologies, Grand Island, New York) for 1 to 3 days. At daily intervals, the level of apoptotic cell death was assessed by propidium iodide staining (20). Activation-induced cell death (AICD) was studied in T cells that had been activated by culturing 2 x 105 naive CD4+ T cells in 1 ml in the presence of 2 x 106 syngeneic APCs and 1 µg/ml HEL46–61 peptide. After 3 days, the activated cells were collected and cultured overnight in medium containing 50 U/ml IL-2. To assay AICD, these cells were cultured with 50 U/ml IL-2 in the presence or absence of plate-bound anti-CD3 (1 µg/ml) for 24 h, and apoptosis was assessed by propidium iodide staining.
In vivo T cell deletion assay
Mice were injected i.p. with PBS or 100 µg of HEL46–61 peptide in a volume of 200 µl. Peptide injections were repeated daily for a total of three doses. The thymus, spleen, and lymph nodes of treated and control mice were harvested for staining and flow cytometric analysis 4 or 8 days after the first injection.
In vitro assay for autoreactive T cells
Graded numbers of purified CD4+ T cells (0–1 x 106) were cultured with 2 x 106 syngeneic APCs in 1 ml of media supplemented with 50 U/ml of IL-2. After 3 to 4 days, 200-µl aliquots of cells were pulsed for 6 h with [3H]TdR to assay proliferation.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first asked whether Fas deficiency or Bcl-2 overexpression
would alter the maturation of T cells, by comparing the numbers and
phenotypes of T cells in the thymi and peripheral lymphoid tissues of
3A9/+, 3A9/lpr, and 3A9/Bcl-2 mice. Vß8 staining was used
to estimate the numbers of T cells expressing the transgenic TCR.
Phenotypic analysis showed that 3A9/lpr mice have a normal
distribution of immature and mature subsets in the thymus. Since the
3A9 TCR is class II MHC restricted, CD4+ cells are
preferentially selected in the 3A9/+ (and 3A9/lpr)
transgenic mice. 3A9/Bcl-2 mice, in contrast, show markedly increased
numbers of total thymocytes, with a significant increase in the numbers
of Vß8+CD4+ cells, as well as
Vß8+CD8+ single-positive cells (Fig. 1
and Table I). Both
Vß8+CD4+ and
Vß8+CD8+ thymocytes in these mice express the
3A9 TCR, as determined by staining with a clonotype-specific mAb (data
not shown). This suggests that Bcl-2 promotes the survival of
thymocytes that are not positively selected because they do not express
CD4, the appropriate T cell coreceptor. It is possible that these
thymocytes express a second (class I-restricted) TCR, which would allow
them to complete maturation. We have not detected expression of other
Vß elements on Bcl-2 transgenic Vß8+CD8+
thymocytes (data not shown), but they may express an endogenous
TCR
-chain (20). Vß8+CD8+ T cells are also
found in significantly increased numbers in the peripheral lymphoid
tissues of 3A9/Bcl-2 mice (Fig. 1 and Table I). More than 80% of these
cells express the 3A9 TCR (data not shown), as well as surface markers
characteristic of mature, naive T cells (L-selectinhigh,
CD69, and CD25low).
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and Table I). In 3A9/Bcl-2 mice the numbers
of these cells is significantly increased. However, in all 3A9 mouse
strains, more than 80% of Vß8+CD4+ cells
also express the 3A9 TCR, and these T cells exhibit identical
proliferative responses and cytokine secretion to Ag in vitro (data not
shown). These findings suggest that Bcl-2 promotes the survival of T
cells in the absence of antigenic stimulation because overexpression of
this molecule leads to dysregulation of T cell maturation and
homeostasis in vivo, but does not alter the response of T cells to Ag
in vitro. Bcl-2 and Fas regulate distinct pathways of T cell apoptosis in vitro
Before analyzing the response of 3A9 T cells to Ag in vivo, we
examined whether a deficiency of Fas or overexpression of Bcl-2 would
affect apoptosis induced under different conditions. T cells undergo
passive cell death when they are cultured without activation signals or
growth factors (21). The assay we have used for this type of cell death
is to culture naive T cells in medium, without adding Ag or cytokines,
and to measure apoptosis by propidium iodide staining at daily
intervals. As shown in Figure 2A, naive 3A9/+ and
3A9/lpr T cells undergo apoptosis, but 3A9/Bcl-2 T cells
remain viable for 3 days in culture under these conditions,
demonstrating that Bcl-2 makes T cells resistant to passive cell death.
Activated T cells can be induced to undergo AICD by exposing them to
high concentrations of Ag or anti-TCR/CD3 Ab in vitro (13, 21, 22, 23, 24).
As shown in Figure 2B, activated 3A9/lpr T cells
remain viable when cultured with high concentrations of anti-CD3,
confirming that they are resistant to AICD (13, 21). In contrast, both
3A9/+ and 3A9/Bcl-2 T cells become apoptotic in this assay,
demonstrating that AICD is not blocked by Bcl-2 expression.
Furthermore, 3A9/+ and 3A9/Bcl-2 T cells become apoptotic when cultured
with an anti-Fas Ab, while Fas-deficient 3A9/lpr T cells
remain viable (data not shown). These results indicate that Fas and
Bcl-2 regulate different pathways of apoptosis. Therefore, TCR
transgenic T cells lacking Fas or constitutively expressing Bcl-2
provide models for studying the consequences of disrupting either of
these two death pathways, and thus for elucidating the functions of
these death pathways in vivo.
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To compare the roles of Fas and Bcl-2 in Ag-induced deletion of
specific T cells in vivo, we first studied T cell deletion in
3A9/lpr and 3A9/Bcl-2 mice treated with high doses of
HEL46–61 peptide i.p. We, and others, have previously
shown that this protocol leads to the deletion of the majority of TCR
transgenic T cells in the thymus, spleen and lymph nodes of wild-type
mice (13, 25). In 3A9 mice treated with peptide, most TCR transgenic T
cells in the spleen and lymph nodes are activated by day 3 (data not
shown). In wild-type mice, these peripheral Ag-specific cells are
subsequently deleted by day 8 (Fig. 3).
The deletion of mature Ag-specific cells is greatly reduced in the
spleen and lymph nodes of 3A9/lpr mice. This is consistent
with earlier studies showing that peripheral T cell deletion is
defective in Fas-deficient mice (13). In contrast, mature Ag-specific T
cells are deleted in Bcl-2 transgenic mice, demonstrating that Bcl-2
does not inhibit this process (Fig. 3). The extent of deletion in
3A9/Bcl-2 mice is typically less than that seen in wild-type mice. A
significant fraction of the surviving T cells express activation
markers (20–60% in Ag-treated 3A9/Bcl-2 mice, 0–30% in similarly
treated 3A9/+ mice; data not shown), indicating that they have
responded to Ag and are not new thymic emigrants. These cells may
represent activated T cells that are not programmed to undergo AICD,
and are instead eliminated by passive cell death when Ag is cleared.
Because Bcl-2 plays a major role in protecting T cells from passive
cell death (Fig. 2, refs. 8, 14), more activated cells would be
expected to survive after peptide treatment in Bcl-2 transgenic mice
than in wildtype mice. Alternatively, Bcl-2 expression may play a minor
role in protecting mature T cells from AICD. This interpretation cannot
be excluded but is not consistent with in vitro data with primary
murine T cells (Fig. 2, ref. 26). Also, developing thymocytes are
deleted by peptide administration in 3A9/+, 3A9/lpr, and
3A9/Bcl-2 mice, suggesting that Fas and Bcl-2 are not involved in
negative selection in the thymus.
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A limitation of this approach is that administering a peptide Ag
in multiple large doses is not a physiologic way of mimicking selection
induced by a self Ag, which is present throughout the development of
the animal. To circumvent this problem we have bred our HEL-specific
3A9/+, lpr, and Bcl-2 mice with mice that express soluble
HEL (approximately 20 ng/ml) in the serum (16). A quarter of the
offspring from these crosses express both the 3A9 TCR and HEL protein,
and are called 3A9 x HEL mice. In these mice, HEL is effectively
a self protein and leads to the deletion of the majority of TCR-bearing
thymocytes. As shown in Table II,
negative selection of HEL ("self" Ag)-reactive 3A9 T cells
occurs equivalently in the thymus of 3A9 x HEL/+ and 3A9 x
HEL/lpr mice. This confirms previous results reported by us
and others that Fas is not required for negative selection in the
thymus (13, 21, 27). The total number of thymocytes in 3A9 x
HEL/Bcl-2 mice is also significantly reduced (Table II). However, the
thymus in these mice is still much larger than in 3A9 x HEL
wild-type or lpr mice. This is not due to a Bcl-2-induced
block in the deletion of TCR transgenic T cells, because the reduction
in CD4+ T cells in the Bcl-2 transgenic mice is equivalent
to that seen in wild-type and Fas-deficient mice. The fraction of
surviving CD4+ cells that express Vß8 is significantly
reduced after Ag exposure, suggesting that most of these
CD4+ cells are not HEL46–61 specific (Table II). An equally striking reduction in Vß8hi-expressing
cells is seen in the double positive thymocyte population in 3A9
x HEL mice, again suggesting that the surviving cells are not Ag
responsive. The increased cellularity seen in the thymi of 3A9 x
HEL/Bcl-2 transgenic mice compared with wild-type and lpr
mice results from the accumulation of a large number of thymocytes that
are CD4-8- or CD8+. Presumably,
these cells do not respond to HEL46–61 and are, therefore,
not negatively selected. The increased number of double-negative
thymocytes found in HEL-transgenic 3A9/Bcl-2 mice compared with
nontransgenic 3A9/Bcl-2 mice is probably not Ag-dependent because these
cells are mostly Vß8- (data not shown). Instead, their
increased numbers may result from their enhanced survival, due to Bcl-2
expression, as well as other compensatory mechanisms. These results
indicate that Bcl-2 overexpression promotes the survival of developing
thymocytes that do not recognize Ag (see also Fig. 1, Table I), but
does not protect from negative selection. Since introducing the cognate
Ag as a circulating protein leads to deletion of T cells in the thymus,
these mice do not contain mature 3A9 T cells. Therefore, they cannot be
used for studying AICD of peripheral T cells.
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It is believed that one consequence of the failure of peripheral T
cell deletion in lpr mice is the accumulation of autoreactive T cells,
which rapidly expand in vitro upon culture without overt stimulation
(28). Since the breedings for the mice, described in experimental
procedures, also resulted in animals not expressing the 3A9 transgene,
it was possible to compare the lpr and Bcl-2-transgenic mice
for the presence of autoreactive T cells. Culture of CD4+ T
cells from lpr mice with syngeneic APCs results in the rapid
outgrowth of autoreactive T cells, but this is not seen with Bcl-2
transgenic T cells (Fig. 4). Expression
of the 3A9 TCR transgene prevents the expansion of autoreactive T cells
in lpr mice (Fig. 4), presumably because of allelic
exclusion of endogenous TCRs, including those that could be
self-reactive. This is the likely reason why the 3A9/lpr mice do not
produce anti-dsDNA autoantibodies and do not develop autoimmune
disease (data not shown). These results demonstrate that Fas, but not
Bcl-2, regulates the survival and/or expansion of autoreactive T cells
in vivo.
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, by 8 to 12 wk of age, lpr
mice (not expressing the 3A9 TCR transgene) contain
CD3+B220+ cells in peripheral lymphoid tissues.
Although Bcl-2-overexpressing mice have enlarged lymph nodes and
spleens, this is not due to an accumulation of abnormal
CD3+B220+ cells. This is additional evidence
that Bcl-2 overexpression does not result in manifestations of
autoimmunity. Also, as seen with autoreactive T cells (Fig. 4),
introducing the 3A9 TCR transgene eliminates the accumulation of
double-negative cells and the lymphoproliferation of lpr
mice (Table III). In contrast, the presence of the 3A9 TCR transgene
does not prevent the accumulation of T cells in Bcl-2 transgenic mice,
indicating that this expansion is not Ag-dependent.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
Thus, Fas and Bcl-2 regulate pathways of apoptosis that are induced by
different stimuli and are presumably biochemically distinct as well.
The question of whether Fas-induced and Bcl-2-regulated pathways of
apoptosis are discrete or intersecting is controversial and not fully
resolved. Some experiments with transfected lymphoid cell lines, and
studies of hepatocytes in Bcl-2 transgenic mice, have shown that Bcl-2
can inhibit Fas-mediated apoptosis (29, 30, 31). Other experiments,
however, show that Bcl-2 does not block apoptosis induced by the Fas
pathway (17, 32, 26), and our results support this conclusion. It is
possible that the effects of Bcl-2 depend on the levels of expression
or vary in different cell types. However, our results, and those of
others (17, 26), show that under conditions where Bcl-2 is functional
in untransformed lymphocytes, because it blocks passive cell death, it
does not prevent AICD. It is also possible that different members of
the Bcl family, e.g. Bcl-2 and Bcl-xL, may have
different functional effects in T cells. However, these molecules
perform identical functions when they are expressed as transgenes in T
cells (33, 34).
Regardless of the mechanistic relationships between the Fas pathway and
Bcl proteins, the approach we have used allows us, for the first time,
to compare the biologic roles of these proteins in an Ag-specific T
cell population whose activation status and functional responses can be
readily manipulated by physiologic stimuli. Our studies using TCR
transgenic mice with defects in Fas or overexpression of Bcl-2 reveal
distinct functions of the two pathways of apoptosis. Fas-dependent
AICD, which is disrupted in lpr mice, appears to be uniquely
involved in deleting mature CD4+ T cells that are
stimulated by large doses of Ags (Fig. 3). Previous studies using
superantigens and TCR transgenic mice are all consistent with this
conclusion (e. g., 13, 21, 27). The accumulation of autoreactive T
cells seen in untreated lpr mice (Fig. 4 and Table III)
suggests that Fas-mediated AICD also controls responses to certain self
Ags. It is likely that these self Ags are abundantly and widely
expressed, since AICD is induced only when numerous T cells respond
coordinately to high concentrations of Ag. The pathologic consequences
of defects in the Fas pathway are autoimmune reactions directed against
such abundant self Ags, presumably triggered by class II-restricted
autoreactive helper T cells.
In contrast to the Fas pathway of AICD, which controls responses to
persistent Ag stimulation, the Bcl-2-regulated pathway of apoptosis
appears to be most important for promoting the survival of lymphocytes,
even cells that do not receive adequate activating stimuli. Thus,
constitutive expression of Bcl-2 results in enhanced survival of naive
T cells cultured without Ag (Fig. 2) and increased accumulation of T
cells that are not positively selected in vivo (Fig. 1 and Table I).
However, Ag-induced deletion of mature CD4+ T cells is not
blocked by Bcl-2, and this is reflected in the absence of autoreactive
T cells in the Bcl-2 transgenic mice (Fig. 4) and the lack of an
autoimmune phenotype in such mice (Table III, and data not shown).
Finally, the results presented here show that Fas and Bcl-2 do not
control deletion of CD4+CD8+ thymocytes induced
by high doses of Ag or by the transgenic expression of a
"self" Ag (Fig. 2 and Table II). Previous studies have shown
that Bcl-2 fails to inhibit thymic deletion of self-reactive
CD8+ T cells, as well as of thymocytes that react with
endogenous superantigens (10). It has also been shown that Fas is not
required for deletion of thymocytes induced by administration of
cognate Ag or superantigens (13, 21, 27), although there may be
particular timepoints or thymocyte subpopulations in which negative
selection is Fas dependent (35, 36). Acute exposure to a peptide
administered at high doses may not be the physiologic counterpart of
exposure to a self Ag. Our results with a transgene-encoded endogenous
"self" Ag are closer to the physiologic situation of negative
selection by self Ags than the studies in which peptides,
superantigens, or polyclonal activators are administered at high doses.
Based on our findings (Table II), we feel it is unlikely that Fas plays
an obligatory role in the self Ag-induced negative selection of the
majority of thymocytes.
The identification of pathways of apoptosis in mature T cells with distinct induction and control mechanisms, and different biologic roles, leads to predictions about the pathophysiologic consequences and practical implications of disrupting or augmenting these pathways. It is likely that Bcl proteins will be the key to prolonging lymphocyte survival, which may be useful for enhancing protective immunologic memory. Modulating the Fas pathway may, on the other hand, be most useful for controlling autoreactivity.
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Footnotes |
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2 Current address: Department of Biology, Room 68-380, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139.
3 Address correspondence and reprint requests to Dr. A.K. Abbas, LMRC-521, 221 Longwood Avenue, Boston, MA 02115.
4 Abbreviations used in this paper: s, soluble; AICD, activation-induced cell death; HEL, hen egg white lysozyme.
Received for publication September 22, 1997. Accepted for publication November 4, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 A. Ayala, C.-S. Chung, J. L. Lomas, G. Y. Song, L. A. Doughty, S. H. Gregory, W. G. Cioffi, B. W. LeBlanc, J. Reichner, H. H. Simms, et al. Shock-Induced Neutrophil Mediated Priming for Acute Lung Injury in Mice: Divergent Effects of TLR-4 and TLR-4/FasL Deficiency Am. J. Pathol., December 1, 2002; 161(6): 2283 - 2294. [Abstract] [Full Text] [PDF]
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Y. Refaeli, L. Van Parijs, S. I. Alexander, and A. K. Abbas Interferon {gamma} Is Required for Activation-induced Death of T Lymphocytes J. Exp. Med., October 7, 2002; 196(7): 999 - 1005. [Abstract] [Full Text] [PDF]
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W. R. Drobyski, R. Komorowski, B. Logan, and M. Gendelman Role of the Passive Apoptotic Pathway in Graft-Versus-Host Disease J. Immunol., August 1, 2002; 169(3): 1626 - 1633. [Abstract] [Full Text] [PDF]
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 M. Melis, L. Siena, E. Pace, M. Gjomarkaj, M. Profita, A. Pirazzoli, M. Todaro, G. Stassi, G. Bonsignore, and A.M. Vignola Fluticasone induces apoptosis in peripheral T-lymphocytes: a comparison between asthmatic and normal subjects Eur. Respir. J., February 1, 2002; 19(2): 257 - 266. [Abstract] [Full Text] [PDF]
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E. Kelly, A. Won, Y. Refaeli, and L. V. Parijs IL-2 and Related Cytokines Can Promote T Cell Survival by Activating AKT J. Immunol., January 15, 2002; 168(2): 597 - 603. [Abstract] [Full Text] [PDF]
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T.-S. Wu, J.-M. Lee, Y.-G. Lai, J.-C. Hsu, C.-Y. Tsai, Y.-H. Lee, and N.-S. Liao Reduced Expression of Bcl-2 in CD8+ T Cells Deficient in the IL-15 Receptor {alpha}-Chain J. Immunol., January 15, 2002; 168(2): 705 - 712. [Abstract] [Full Text] [PDF]
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 T. J. Fry, B. L. Christensen, K. L. Komschlies, R. E. Gress, and C. L. Mackall Interleukin-7 restores immunity in athymic T-cell-depleted hosts Blood, March 15, 2001; 97(6): 1525 - 1533. [Abstract] [Full Text] [PDF]
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T. Wekerle, J. Kurtz, M. H. Sayegh, H. Ito, A. D. Wells, S. Bensinger, J. Shaffer, L. A. Turka, and M. Sykes Peripheral Deletion After Bone Marrow Transplantation with Costimulatory Blockade Has Features of Both Activation-Induced Cell Death and Passive Cell Death J. Immunol., February 15, 2001; 166(4): 2311 - 2316. [Abstract] [Full Text] [PDF]
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C.-H. Wei, H. Yagita, M. G. Masucci, and V. Levitsky Different Programs of Activation-Induced Cell Death Are Triggered in Mature Activated CTL by Immunogenic and Partially Agonistic Peptide Ligands J. Immunol., January 15, 2001; 166(2): 989 - 995. [Abstract] [Full Text] [PDF]
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H. N. Shi, H. Y. Liu, and C. Nagler-Anderson Enteric Infection Acts as an Adjuvant for the Response to a Model Food Antigen J. Immunol., December 1, 2000; 165(11): 6174 - 6182. [Abstract] [Full Text] [PDF]
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 L. Majlessi and G. Bordenave Non-overlapping Fas- and BCL-2-regulated death pathways in IgG2ab-producing B cells Int. Immunol., July 1, 2000; 12(7): 969 - 976. [Abstract] [Full Text] [PDF]
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 M. J. Pinkoski, T. Brunner, D. R. Green, and T. Lin Fas and Fas ligand in gut and liver Am J Physiol Gastrointest Liver Physiol, March 1, 2000; 278(3): G354 - G366. [Abstract] [Full Text] [PDF]
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 K. J. Hamann, J. E. Vieira, A. J. Halayko, D. Dorscheid, S. R. White, S. M. Forsythe, B. Camoretti-Mercado, K. F. Rabe, and J. Solway Fas cross-linking induces apoptosis in human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L618 - L624. [Abstract] [Full Text] [PDF]
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K. Newton and A. Strasser Ionizing Radiation and Chemotherapeutic Drugs Induce Apoptosis in Lymphocytes in the Absence of FAS or Fadd/Mort1 Signaling: Implications for Cancer Therapy J. Exp. Med., January 3, 2000; 191(1): 195 - 200. [Abstract] [Full Text] [PDF]
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A. Schwarting, G. Tesch, K. Kinoshita, R. Maron, H. L. Weiner, and V. R. Kelley IL-12 Drives IFN-{gamma}-Dependent Autoimmune Kidney Disease in MRL-Faslpr Mice J. Immunol., December 15, 1999; 163(12): 6884 - 6891. [Abstract] [Full Text] [PDF]
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W. Van Molle, G. Denecker, I. Rodriguez, P. Brouckaert, P. Vandenabeele, and C. Libert Activation of Caspases in Lethal Experimental Hepatitis and Prevention by Acute Phase Proteins J. Immunol., November 15, 1999; 163(10): 5235 - 5241. [Abstract] [Full Text] [PDF]
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J. D. Milner, S. C. Kent, T. A. Ashley, S. B. Wilson, J. L. Strominger, and D. A. Hafler Differential Responses of Invariant V{alpha}24J{alpha}Q T Cells and MHC Class II-Restricted CD4+ T Cells to Dexamethasone J. Immunol., September 1, 1999; 163(5): 2522 - 2529. [Abstract] [Full Text] [PDF]
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N. C. Hebib, O. Deas, M. Rouleau, A. Durrbach, B. Charpentier, F. Beaujean, J.-P. Vernant, and A. Senik Peripheral Blood T Cells Generated After Allogeneic Bone Marrow Transplantation: Lower Levels of Bcl-2 Protein and Enhanced Sensitivity to Spontaneous and CD95-Mediated Apoptosis In Vitro. Abrogation of the Apoptotic Phenotype Coincides With the Recovery of Normal Naive/Primed T-Cell Profiles Blood, September 1, 1999; 94(5): 1803 - 1813. [Abstract] [Full Text] [PDF]
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S. Brochu, B. Rioux-Masse, J. Roy, D.-C. Roy, and C. Perreault Massive Activation-Induced Cell Death of Alloreactive T Cells With Apoptosis of Bystander Postthymic T Cells Prevents Immune Reconstitution in Mice With Graft-Versus-Host Disease Blood, July 15, 1999; 94(2): 390 - 400. [Abstract] [Full Text] [PDF]
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 H. GUDMUNDSDOTTIR and L. A. TURKA T Cell Costimulatory Blockade: New Therapies for TransplantRejection J. Am. Soc. Nephrol., June 1, 1999; 10(6): 1356 - 1365. [Abstract] [Full Text]
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M. M. Di Somma, F. Somma, M. S. G. Montani, R. Mangiacasale, E. Cundari, and E. Piccolella TCR Engagement Regulates Differential Responsiveness of Human Memory T Cells to Fas (CD95)-Mediated Apoptosis J. Immunol., April 1, 1999; 162(7): 3851 - 3858. [Abstract] [Full Text] [PDF]
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Y.-C. Lim, L. Henault, A. J. Wagers, G. S. Kansas, F. W. Luscinskas, and A. H. Lichtman Expression of Functional Selectin Ligands on Th Cells Is Differentially Regulated by IL-12 and IL-4 J. Immunol., March 15, 1999; 162(6): 3193 - 3201. [Abstract] [Full Text] [PDF]
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C.-L. Chu, S.-S. Chen, T.-S. Wu, S.-C. Kuo, and N.-S. Liao Differential Effects of IL-2 and IL-15 on the Death and Survival of Activated TCR{gamma}{delta}+ Intestinal Intraepithelial Lymphocytes J. Immunol., February 15, 1999; 162(4): 1896 - 1903. [Abstract] [Full Text] [PDF]
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