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Department of Biology and the Cancer Center, University of California at San Diego, La Jolla, CA 92093
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In addition to a high avidity TCR stimulus, negative selection also requires costimulatory signals from APC (14, 15). The identification of specific costimulators, however, has been very controversial. Although CD28, Fas, and TNFR have been implicated in negative selection (16, 17, 18), thymocyte deletion is apparently intact in mice lacking these molecules (18, 19, 20). The receptor/ligand pair that has emerged as a master regulator of negative selection in several systems is CD40/CD40 ligand (L).3 Negative selection of CD4+ T cells by class II MHC molecules is profoundly defective in CD40- or CD40L-null mice (21, 22, 23, 24). Since CD40 stimulation of APC increases the expression of many costimulatory molecules, we have hypothesized that CD40 regulates several costimuli that are required for negative selection (21, 25). These costimuli could include the CD28 ligands CD80 and CD86, adhesion molecules such as CD54 (ICAM-1) or CD58 (LFA-3), death receptor ligands such as Fas ligand (FasL), and/or cytokines such as TNF and IL-12 (26). Recently, we investigated whether several costimulators might be jointly controlling thymocyte deletion. Using a combination of blocking Abs in fetal thymus organ culture (FTOC), we found that CD5, the CD28 ligands CD80 and CD86, and TNF cooperatively regulated negative selection of CD4+ T cells by class II MHC in three different systems (27). Correspondingly, Kishimoto and Sprent (28) found that CD28, CD43 (a receptor for CD54), and Fas were involved in negative selection of medullary thymocytes induced by injection of bacterial superantigen or peptide Ag into TCR-transgenic mice. Taken together, these studies suggest that CD40 stimulation of APC induces costimuli that cooperatively regulate negative selection of CD4+ T cells, including at least CD80, CD86, CD54, TNF, and FasL. CD40 stimulation of APC may also induce CD5L; however, the expression and regulation of CD5L are presently unknown (29, 30, 31).
Although these experiments provided strong evidence for the action of
several costimulators in negative selection, we wished to demonstrate a
role for these molecules in an in vivo model where thymocyte deletion
occurs in response to an autoantigen. Such a model is both a more
stringent test of costimulator involvement in negative selection and
also more applicable to studies of autoimmunity. Therefore, we examined
thymocyte deletion caused by endogenous superantigens (SAg), which are
produced from an open reading frame in the 3' long terminal
repeat of various mouse mammary tumor viruses (Mtv) (32, 33). SAg delete thymocytes bearing specific TCR-V
chains, and
this deletion has been studied extensively as a model of
autoantigen-induced negative selection (33, 34). We chose
this model for our investigation because it is a physiologically
natural model of negative selection, in that there is no manipulation
of TCR or Ag expression in the thymus. Moreover, CD40- or CD40L-null
mice are defective in SAg-mediated deletion (21, 23) and
thus we could directly compare negative selection in costimulator-null
mice to that seen in CD40L-null mice. Surprisingly, we found that the
costimulators CD5 and CD28 are required in only one of three models of
SAg-dependent negative selection examined. Our results further indicate
that the involvement of costimulatory molecules in negative selection
in vivo is extraordinarily complex and will probably be different for
each system that is examined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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CD5-null, CD28-null, BALB/c and D1.LP mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained in our animal facilities under specific pathogen-free conditions. CD40L-null mice that had been backcrossed to C57BL/6J were obtained from Randolph Noelle (Dartmouth College, Hanover, NH).
Abs and flow cytometric analysis
Mice were sacrificed by CO2 inhalation,
and lymphocytes were released from thymus, spleen, and/or mesenteric
lymph nodes as previously described (18). Surface
expression of CD5, CD28, CD4, CD8, heat-stable Ag (HSA), CD44,
CD62L, and TCRV chains was determined by Ab staining and flow
cytometry with collection of 30,000–100,000 live cells
(18). Abs to CD5, CD28, V5.1/5.2 (MR9-4), V6
(RR4-7), V8.1/8.2 (MR5-2), V11 (RR3-15), HSA, CD44, and CD62L
were purchased from BD PharMingen (San Diego, CA). Anti-CD4-PE and
anti-CD8-Tri-Color were purchased from Caltag (Burlingame,
CA).
PCR and Southern blotting
Mtv-6, -8, and -9 were detected by PCR of tail DNA (35). Mtv-7 was detected by Southern blot analysis of tail DNA, as described elsewhere (33).
Statistical analyses
Statistical analyses were performed by the Biostatistics Shared Resource Facility (Elizabeth Gilpin, Cancer Center, University of California, San Diego). Examination of the data for the variables of interest indicated that an ANOVA would be appropriate for establishing whether there were differences among groups of mice. Accordingly, if the overall F ratio was significant, costimulator-null mice were compared with wild-type mice using Dunnett’s test to control for multiple testing (36). A further comparison of CD5-/-CD28-/- mice to CD5-/- mice was also performed in some cases using a modified t test (Duncan’s procedure).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To investigate whether costimulators are required for negative selection in vivo, we examined thymocyte deletion in response to SAg in three model systems. We chose to analyze the roles of CD5 and CD28, since these molecules exhibited a strong cooperative effect on negative selection in our previous experiments in FTOC (27). We obtained CD5-/- and CD28-/- mice on the C57BL/6 background (H2b) and crossed them to BALB/c (H2d) or D1.LP mice (H2b) for all of the experiments reported here. Additionally, we analyzed very young mice (ages 2–3 wk for the BALB/c experiments and 2–5 wk for the D1.LP experiments) to avoid any cumulative effects of peripheral tolerance on the T cell repertoire. To obtain enough littermates for these experiments, the wild-type mice were heterozygous at both loci (CD5+/- CD28+/-), CD5-null mice were CD5-/- CD28+/- and CD28-null mice were CD5+/- CD28-/-.
T cell repertoire in CD5- and CD28-null mice
No significant differences in total numbers of thymocytes or
splenocytes were noted in these animals. However, the percentage of CD4
and CD8 T cells was increased in the thymus and spleen of
CD5-/- CD28-/- mice
(Table I
). Both
CD4+ and CD8+ thymocytes
were increased in CD5-null mice, and CD4+
thymocytes were further increased in CD5-/-
CD28-/- mice. Although Table I reports only the
results from the H2b mice from the
(CD5-/- CD28-/- x
BALB/c) crosses, similar results were obtained in the
H2b/d mice from these crosses and also in the
older H2b mice studied in the D1.LP model (data
not shown).
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Deletion of V11+ thymocytes and T cells by Mtv-8,9
CD5- and CD28-null mice on the C57BL/6 background
(H2b, Mtv-8, -9, -17, -30+)
were crossed to BALB/c mice (H2d, Mtv-6, -8,
-9+) to obtain mice that were
H2b or H2b/d and that
expressed two copies of Mtv-8,9 and one copy of Mtv-6. Mtv-6 deletes
V3- and V5-bearing T cells, and Mtv-8,9 delete V5-, V11-,
and V12-bearing T cells (43). Since Mtv-30 is probably
not expressed, and since Mtv-17 has very little effect on V11
deletion in comparison to Mtv-8,9 (43), we did not screen
for Mtv-17,30. An examination of SAg-mediated deletion previously
showed that CD40L-null mice are profoundly deficient in deletion of
V5+ and V11+
thymocytes, partially deficient in deletion of
V12+ thymocytes, but not at all deficient in
deletion of V3+ thymocytes (21).
Correspondingly, V3+ thymocytes were not
rescued from SAg-induced deletion in CD5-/-
CD28-/- mice (data not shown). Thus, we focused
our examination on Mtv-6,8,9-mediated deletion of
V5+ and V11+ T cells
for these experiments (summary in Table II). Since SAg-mediated deletion is more
efficient in the presence of H2-E, we first analyzed
Mtv-6,8,9-induced-deletion in H2b/d
mice.
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shows the V11 profile of
thymocytes obtained from these mice. In wild-type mice, negative
selection induced by Mtv-8,9/H2-E caused the percentage of
V11+ thymocytes to decrease from 6 to 4%
among the CD4+ cells and from 5 to 2% among the
CD8+ cells (Fig. 1, compare wild-type
H2b to wild-type H2b/d). As
expected, CD40L-null, H2b/d mice exhibited a
complete rescue from Mtv-8,9-induced deletion of both
CD4+ and CD8+
V11-bearing thymocytes (Fig. 1, compare
CD40L-/- H2b/d to
wild-type H2b/d and wild-type
H2b). Interestingly,
CD28-/- or CD5-/-
CD28-/- H2b/d mice
exhibited a partial rescue of
V11+CD4+ thymocytes from
negative selection (Fig. 1, top, compare mice in
H2b/d group). This rescue appeared to be due
solely to the lack of CD28, since increased rescue of
V11+CD4+
cells was not consistently observed in mice lacking both
CD5 and CD28. Since the total numbers of thymocytes were similar in
wild-type or costimulator-null mice, the increased percentage of
V11+CD4+ thymocytes
represents an increase in the total number of these cells. For example,
in four experiments, the average number of
V11+CD4+ thymocytes
obtained was 1.9 ± 0.4 x 105,
2.0 ± 0.2 x 105, 2.6 ± 0.7
x 105, and 3.3 ± 0.2 x
105 cells for the wild-type,
CD5-/-, CD28-/-, and
CD5-/-CD28-/- mice,
respectively. These results suggest that CD28 is involved in
Mtv-8,9-induced deletion of
V11+CD4+ thymocytes.
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11+CD8+
thymocytes were rescued from negative selection in CD40L-null mice,
they were not significantly rescued in the costimulator-null mice (Fig. 1
, bottom, H2b/d mice). Thus, CD5 and
CD28 are not required for Mtv-8,9-induced deletion of
V11+CD8+ thymocytes.
Instead, CD40 stimulation of APC apparently induces costimuli that act
through other receptors to delete these cells.
Fig. 2 shows the V11 profiles of the
splenocytes obtained from these mice. In previous reports, the cells
that were rescued from negative selection in CD40L-null mice did not
accumulate in the periphery; rather, the autoreactive cells were
apparently deleted by uncharacterized mechanisms of peripheral
tolerance (21, 23). However,
CD4+V11+ T cells were
present in the periphery of the CD40L-/- mice
in these experiments (Fig. 2, top). One possibility is that
CD4+ cells were still present because the mice in
this analysis were quite young. However, we note that even these young
CD40L-/- mice still deleted the peripheral
CD8+V11+ cells (Fig. 2, bottom). The mechanisms of peripheral tolerance underlying
these differing effects have not yet been characterized.
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11+, but not
CD8+V11+, T cells in
their spleens (Fig. 2). Although there appeared to be an increased
percentage of V11+CD4+
splenocytes in CD28-/- mice, the difference was
not statistically significant. Instead, we noted a better accumulation
in CD5-/- CD28-/- mice
as compared with CD28-/- mice. It is possible
that CD5 does act in conjunction with CD28 in thymic deletion, but that
the effect is small and is only seen as the cells accumulate in the
periphery. Alternatively, CD5 could be working through mechanisms of
peripheral tolerance to induce accumulation of these cells. Taken
together, the results in Figs. 1 and 2 indicate that both CD5 and CD28
can contribute to Mtv-8,9-induced deletion of
CD4+V11+ cells. However,
rescue of V11+ cells was always more profound
in CD40L-null mice; thus, other costimulators must also be contributing
to negative selection in this system (summary in Fig. 7).
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), we
considered the possibility that the rescue of
V11+ cells in CD5-/-
CD28-/- mice was not Mtv dependent. Therefore,
we examined V8.1/8.2 profiles, since these T cells are not deleted
by Mtv-6, -8, or -9 (43), and this population is therefore
commonly used as a control for Mtv-6,8,9-specific deletion
(44, 45, 46). The percentage of
V8.1/8.2+ cells did not increase in the
costimulator-null mice (Fig. 3). In fact,
the percentage of V8.1/8.2+ cells among the
CD4+ population decreased significantly in the
CD28-/- and
CD5-/-CD28-/-, but not
the CD5-/- mice (Fig. 3, top). This
result would be expected if V11+ T cells are
being rescued from Mtv-8,9-induced deletion, because it is well
documented that the V8.1/8.2 population behaves in a compensatory
fashion in the presence of these SAg (43, 44, 45, 46). Similar
results were observed in the V8.1/8.2 profile of the splenocytes as
well (data not shown). Thus, the rescue of the V11 population in
CD28-/- and CD5-/-
CD28-/- H2b/d mice
appears to be Mtv-8,9 dependent.
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It was possible that the
V11+CD4+ cells rescued
from deletion in the costimulator-null mice were not truly mature or
expressed an activated phenotype. We therefore examined these cells for
their HSA, CD44, and CD62L profile (Fig. 4). HSA is down-regulated as thymocytes
progress from the CD4+CD8+
(double-positive) stage to the mature CD4+ or
CD8+ stage (e.g., compare Fig. 4, G
and H). In H2b mice, 6.0% of the
CD4+ thymocytes were
V11+, and 32% of these cells were
HSAlow (Fig. 4, A and D).
In contrast, CD5-/-,
H2b/d mice exhibited deletion of their
CD4+V11+ thymocytes and
only 10% of those remaining were HSAlow (Fig. 4, B and E). As expected,
V11+CD4+ thymocytes were
rescued in H2b/d, CD5-/-
CD28-/- mice and 28% of these were
HSAlow (Fig. 4, C and F).
Thus, the HSA profile of the thymocytes rescued from deletion matched
the HSA profile of the
V11+CD4+ cells that
matured in the H2b mice. Correspondingly, the
V11+CD4+ splenocytes in
the CD5-/- CD28-/- mice
appeared to be mature naive T cells, in that they displayed a normal
CD44 and CD62L profile (Fig. 4, K and N, and data
not shown). In conclusion, the rescued
V11+CD4+ cells in the
costimulator-null mice are both mature and naive based on these
parameters.
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5+ thymocytes and T cells by Mtv-6,8,9
We next examined V5 profiles in these same mice, expecting to
see similar results as those obtained for the V11 population.
Surprisingly, quite different results were obtained. First,
CD4+V5+, but not
CD8+V5+, thymocytes were
completely rescued from deletion in CD40L-null mice (Fig. 5, H2b/d mice).
Thus, CD40L is not significantly involved in negative selection of the
V5+CD8+ population.
Moreover, unlike the results above, CD28 and CD5 contributed either
marginally or not at all to deletion of
CD4+V5+ thymocytes (Fig. 5, H2b/d mice). Similar results were obtained in
splenocytes (data not shown, but see Table II). Thus, it appears that
CD5 and CD28 are not required for deletion of
CD4+V5+ thymocytes by
Mtv-6,8,9. Rather, CD40 stimulation of APC apparently induces costimuli
that act through other receptors to delete these cells (Fig. 7).
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5+ thymocytes may not require CD5 and CD28.
However, this is unlikely because in the cases where we screened for
Mtv-6 expression, we did not observe a significant effect of Mtv-6 on
V5 deletion over and above that already due to Mtv-8,9 (data not
shown). Correspondingly, single Mtv mice reveal that Mtv-9 alone can
delete 80–98% of the
V5+CD4+ T cells
(43). A more likely possibility is that deletion of
V5+ or V11+
thymocytes occurs at different stages of thymocyte development or is
regulated by different APC. V11 deletion occurs somewhere during the
transition between immature
CD4+CD8+ precursors and
mature medullary thymocytes (44), whereas V5 deletion
apparently occurs in the thymic medulla (47).
Interestingly, bone marrow-derived APC are required for V11
deletion (45), whereas V5 deletion can be mediated by
bone marrow-derived APC or medullary epithelium (48, 49, 50).
Thus, it is possible that V5 deletion by medullary epithelium is not
CD5/CD28-dependent and that a requirement for participation of these
costimulators is thereby overcome and the thymocytes are deleted.
However, this explanation does not agree with data indicating that CD28
is involved in other models of medullary thymocyte-negative selection
(28).
Deletion of V6+ thymocytes and T cells by Mtv-7
Due to the differences in costimulator involvement in negative
selection in the systems described above, we investigated the role of
CD5/CD28 in another system of SAg-mediated deletion. Deletion of
V6+ T cells occurs in response to Mtv-7 in
both H2-E+ and H2-E- mice
(51). However, deletion in H2-E-
mice (e.g., the D1.LP strain) is weaker and occurs over a period of
several weeks. This type of negative selection is completely rescued in
CD40-null mice, whereas the stronger
H2-E+/Mtv-7-dependent deletion is only partially
rescued in CD40-null mice (23). Our hypothesis was that
roles for costimulators would be more apparent in a system of weak
negative selection. To our surprise, this was not the case.
For these experiments, we compared deletion of
V6+ cells in the following D1.LP mice
(H2-Ab, H2-E-) from 2 to 5
wk of age: 1) CD5-/-
CD28-/-, Mtv-7-
(negative control for deletion); 2) CD40L+/-,
Mtv-7+ (positive control for deletion); 3)
CD40L-/-, Mtv-7+ (control
for rescue from deletion); and 4) CD5-/-
CD28-/-, Mtv-7+. As
expected, nearly complete rescue of
CD4+V6+ and
CD8+V6+ cells from
negative selection was observed in the thymi of
CD40L-/- mice expressing Mtv-7 (Fig. 6). For example, the percentage of
V6+ cells among CD4+
thymocytes in CD40L+/- littermates expressing
Mtv-7 (large dashed line with filled triangles) declined from 7.6% at
age 2 wk to 5.5% at age 5 wk. In contrast, CD40L-null mice expressing
Mtv-7 retained high levels of these cells (8–10%, thick line with
open triangles). In fact, there was virtually no Mtv-7-induced negative
selection in the CD4+ or
CD8+ thymocytes from CD40L-null mice (compare
thick line to Mtv-7- control, small dashed line
with filled squares). Some of the cells rescued from negative selection
in CD40L-null mice also accumulated in the periphery (data not shown,
but see summary in Table II).
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6+ cells seen in
CD40L-/- mice, no rescue whatsoever was
observed in CD5-/-
CD28-/- mice, even in the youngest mice
examined where deletion was not yet complete.
CD5-/- CD28-/- animals
lacking Mtv-7 (small dashed lines with filled squares in Fig. 6, top) possessed 8–10% V6+ cells
among their CD4+ thymocytes or T cells (data not
shown). In CD5-/-
CD28-/- animals expressing Mtv-7, deletion of
V6+ cells proceeded normally (Fig. 6, compare
plain line with open squares to CD40L+/-,
Mtv-7+ control). Similar results were observed in
CD5-/- or CD28-/-
animals as well (data not shown, but see Table II). Thus, CD5 and CD28
are not required for Mtv-7-induced thymocyte deletion; again, CD40
stimulation of APC apparently induces costimuli that act through
different receptors to delete these cells (Fig. 7).
Why are CD5/CD28 involved in deletion of V11+
cells by Mtv-8,9, but not in deletion of V6+
cells by Mtv-7? An obvious possibility is the strength of the signal
induced by the different SAg. However, Mtv-7 deletion in an
H2-E-negative environment is thought to be a weaker signal than Mtv-8,9
deletion on H2-E. Thus, one would expect the Mtv-7 model to be more
costimulator dependent. For example, Dautigny et al. (22)
found that CD54 (ICAM-1) and Fas were involved in the "weak"
Mtv-9-induced deletion of V5+ thymocytes in
H2-E- mice. Thus, signal strength is not a
likely explanation for the different costimulator requirements in these
systems.
Another possibility is that deletion of V6+
and V11+ thymocytes depend on different APC.
Both models of negative selection apparently require bone
marrow-derived cells (45). In an FTOC model, both
dendritic cells and B cells were required to induce deletion of
V6+ cells; it was thought that B cells express
large quantities of SAg, which they then pass to dendritic cells
(46). Similarly, Frey et al. (52) showed that
B cells were likely required for deletion of
V11+ cells. However, V6 and V11 deletion
both proceed normally in B cell-deficient mice (53).
Moreover, recent studies of thymic dendritic cells show that they do
express Mtv-7,8 by PCR and functional studies (54).
Finally, Webb and Sprent (55) showed that CD8 T cells were
responsible for inducing neonatal tolerance to Mtv-7. Thus, the APC
that induce deletion in these systems are still unknown, and we
currently do not understand why costimulator requirements are different
in these two systems.
Summary
CD40L was clearly involved in thymic deletion in all three models
examined, except for deletion of
V5+CD8+ cells (Fig. 7).
Thus, CD40/CD40L has again emerged as a master regulator of class II
MHC-mediated negative selection. However, the precise costimulatory
molecules regulated by CD40 that are required for negative selection in
vivo remain elusive. Only in the case of negative selection of
V11+CD4+ cells were CD5
and CD28 shown to be significantly involved. Here, CD40 is probably
regulating the CD28 ligands CD80 and CD86 (26), but the
expression and regulation of CD5L are unknown (29, 30, 31). In
the other models of negative selection examined here, CD40 may induce
other costimuli required for thymocyte deletion, perhaps CD54 (ICAM-1),
FasL, or TNF (22, 27, 28). These molecules could regulate
negative selection separately or in combination with CD5 and CD28.
Based on these results, we predict that a complex array of
costimulatory receptors are involved in negative selection in vivo and
that the cohort of receptors involved will vary depending on the timing
of negative selection, the Ag, the signal strength, the
APC, and whether Ag presentation occurs on class I or class II MHC
molecules.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Dawne M. Page, Department of Biology and the Cancer Center, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0687.
3 Abbreviations used in this paper: L, ligand; FTOC, fetal thymic organ culture; SAg, superantigen; Mtv, mouse mammary tumor virus; HSA, heat-stable Ag.
Received for publication December 4, 2000. Accepted for publication March 9, 2001.
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S.-Y. Na, A. Patra, Y. Scheuring, A. Marx, M. Tolaini, D. Kioussis, B. Hemmings, T. Hunig, and U. Bommhardt Constitutively Active Protein Kinase B Enhances Lck and Erk Activities and Influences Thymocyte Selection and Activation J. Immunol., August 1, 2003; 171(3): 1285 - 1296. [Abstract] [Full Text] [PDF]
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Y. Yan, T. Devos, L. Yu, G. Xia, O. Rutgeerts, J. Goebels, C. Segers, Y. Lin, M. Vandeputte, and M. Waer Pathogenesis of Autoimmunity After Xenogeneic Thymus Transplantation J. Immunol., June 15, 2003; 170(12): 5936 - 5946. [Abstract] [Full Text] [PDF]
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J. E. Buhlmann, S. K. Elkin, and A. H. Sharpe A Role for the B7-1/B7-2:CD28/CTLA-4 Pathway During Negative Selection J. Immunol., June 1, 2003; 170(11): 5421 - 5428. [Abstract] [Full Text] [PDF]
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C. Brossard, M. Semichon, A. Trautmann, and G. Bismuth CD5 Inhibits Signaling at the Immunological Synapse Without Impairing Its Formation J. Immunol., May 1, 2003; 170(9): 4623 - 4629. [Abstract] [Full Text] [PDF]
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J. Wang and Y.-X. Fu LIGHT (a Cellular Ligand for Herpes Virus Entry Mediator and Lymphotoxin Receptor)-Mediated Thymocyte Deletion Is Dependent on the Interaction Between TCR and MHC/Self-Peptide J. Immunol., April 15, 2003; 170(8): 3986 - 3993. [Abstract] [Full Text] [PDF]
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R. Yucel, H. Karsunky, L. Klein-Hitpass, and T. Moroy The Transcriptional Repressor Gfi1 Affects Development of Early, Uncommitted c-Kit+ T Cell Progenitors and CD4/CD8 Lineage Decision in the Thymus J. Exp. Med., April 7, 2003; 197(7): 831 - 844. [Abstract] [Full Text] [PDF]
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X.-Z. Yu, P. J. Martin, and C. Anasetti CD28 Signal Enhances Apoptosis of CD8 T Cells After Strong TCR Ligation J. Immunol., March 15, 2003; 170(6): 3002 - 3006. [Abstract] [Full Text] [PDF]
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H. J. Cho, S. G. Edmondson, A. D. Miller, M. Sellars, S. T. Alexander, S. Somersan, and J. A. Punt Cutting Edge: Identification of the Targets of Clonal Deletion in an Unmanipulated Thymus J. Immunol., January 1, 2003; 170(1): 10 - 13. [Abstract] [Full Text] [PDF]
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 T. M. Onami, M.-Y. Lin, D. M. Page, S. A. Reynolds, C. D. Katayama, J. D. Marth, T. Irimura, A. Varki, N. Varki, and S. M. Hedrick Generation of Mice Deficient for Macrophage Galactose- and N-Acetylgalactosamine-Specific Lectin: Limited Role in Lymphoid and Erythroid Homeostasis and Evidence for Multiple Lectins Mol. Cell. Biol., July 15, 2002; 22(14): 5173 - 5181. [Abstract] [Full Text] [PDF]
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J.-X. Gao, H. Zhang, X.-F. Bai, J. Wen, X. Zheng, J. Liu, P. Zheng, and Y. Liu Perinatal Blockade of B7-1 and B7-2 Inhibits Clonal Deletion of Highly Pathogenic Autoreactive T Cells J. Exp. Med., April 15, 2002; 195(8): 959 - 971. [Abstract] [Full Text] [PDF]
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