| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Emory Vaccine Center and Department of Microbiology and Immunology,
Department of Surgery, Carlos and Marguerite Mason Transplantation Research Center, and
Department of Psychiatry, Emory School of Medicine, Atlanta, GA 30322;
Department of Pathology and Laboratory Medicine, University of California School of Medicine, Los Angeles, CA 90095; and
¶ Center for Blood Research, Harvard School of Medicine, Boston, MA 02115
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The abundant T cell surface glycoprotein CD43 (sialophorin, gp115,
leukosialin) is a transmembrane protein consisting of a highly
O-glycosylated extracellular domain of 235 amino acids, a
transmembrane domain of 23 amino acids, and an intracytoplasmic domain
of 123 amino acids (4). Posttranslational modifications
result in two glycoforms of CD43. The mAb S7 recognizes the
lower-molecular mass (115 kDa) glycoform (5), while the
mAb 1B11 was initially characterized as recognizing the
activation-associated, high-molecular mass (130 kDa) glycoform of CD43
(5). This high-molecular mass glycoform bears core 2
O-glycans, an oligosaccharide structure that can be created
by the action of the core 2
-1–6-N-acetylglucosaminyltransferase (6).
Recently, one report has shown that 1B11 recognizes a novel CD8 T
cell-restricted CD45RB epitope that is independent of core 2
O-glycans on naive CD8 T cells (7). Thus, it
was unclear which glycoprotein(s) 1B11 was binding on activated
Ag-specific CD8 T cells.
Although CD43 is one of the most abundant T cell surface glycoproteins, its functions remain controversial. It has been purported to have antiadhesive as well as proadhesive functions in T cell trafficking (8, 9, 10, 11). Additionally, CD43 has been shown to play a role in T cell activation, although this, too, remains unclear. Ab cross-linking experiments suggested a costimulatory role in vitro (12); however, other groups suggested a negative regulatory role in T cell activation (8, 13). Most recently, it has been shown that CD43 is excluded from the immunological synapse during T cell activation, and this exclusion appears to be mediated by an ezrin-radixin-moesin-dependent mechanism(s) (14, 15, 16, 17).
To understand the role of CD43 on effector CD8 T cells during an immune response, we generated Ag-specific effector CD8 T cells in CD43-deficient mice. Surprisingly, there was a complete absence of the up-regulation of 1B11 binding on these cells, firmly establishing that the up-regulated binding of 1B11 observed on effector CD8 T cells in vivo requires the expression of CD43. We examined the course of a viral immune response in CD43-/- mice and found that while CD43 plays a positive regulatory role in the costimulation and trafficking of naive T cells in vivo, it appears to play a negative regulatory role in the waning/down-modulation of effector T cell responses. These results suggest a dynamic role of CD43 during an immune response that is reflective of its dynamic regulation and modification during T cell activation, death, and homeostasis.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD43-/- mice and B6.129 control mice (CD43+/+) were purchased from The Jackson Laboratory (Bar Harbor, ME) and bred in-house under specific pathogen-free conditions. For acute LCMV responses, naive adult mice (>5 wk) were infected with 2 x 105 PFU of LCMV-Armstrong i.p. For LCMV disease studies, adult mice (4–6 wk old) were infected with 1 x 102 or 1 x 105 PFU LCMV-Armstrong intracranially (i.c.). For chronic studies, adult mice (>5 wk old) were infected with 2 x 106 PFU LCMV clone 13 i.v.
Surface/tetramer staining, flow cytometry, and direct ex vivo CTL assay
Spleens were harvested from mice and passed through a screen in
10% FCS in RPMI with antibiotics and 2-ME. RBCs were lysed and cells
were washed and counted for total cell yields. For immunostaining,
1 x 106 cells were stained in 96-well
U-bottom plates. All mAbs and apoptosis reagents (anti-CD8
-PE,
anti-CD62L-FITC, anti-CD44-FITC, S7-FITC, S7-PE, 1B11-FITC,
anti-Bcl-2-FITC, anti-bromodeoxyuridine (BrdU)-FITC, Annexin
V-FITC, and 7-amino actinomycin D (7-AAD)) were purchased from BD
PharMingen (San Diego, CA.) Production of MHC class I tetramers
DbNP396–404 and
Dbgp33–41-allophycocyanin were done as
previously described (1). PNA-FITC was purchased from
Sigma-Aldrich (St. Louis, MO). Flow cytometry was performed on a
FACSCalibur (BD Biosciences, Mountain View, CA). LCMV-specific
CTL activity was determined by a 5-h 51Cr release
assay as previously described (1).
Immunohistochemistry
CD8 T cell infiltrates in the brain were assessed by
immunohistochemistry. Brains were harvested from mice and cut in half.
One half was used to isolate CNS mononuclear cells and the other half
was quick-frozen and stored at -70°C until sectioned on a cryostat.
Sagittal brain sections were prepared from frozen tissue, ethanol-fixed
for 20 min, transferred to PBS, incubated with DAKO block (DAKO,
Carpinteria, CA) for 45 min to block endogenous peroxidase, followed by
a 15-min block with 5% rabbit serum in PBS, and stained with
anti-CD8 and anti-CD8 Abs (BD PharMingen) for 90
min. Sections were washed with PBS, incubated for 45 min with
biotinylated rabbit anti-rat Ab (Jackson ImmunoResearch
Laboratories, West Grove, PA), and developed with the ABC Elite kit
(Vector Laboratories, Burlingame, CA) and DAB. Sections were
counterstained with Mayer’s hematoxylin. Images were analyzed using
x4 and x20 objectives and captured by digital photomicroscopy for
final output.
Isolation of CNS mononuclear cells
Brain tissue was harvested from mice in 1% FCS in RPMI, transferred to an ice-cold 7-ml Tenebroeck glass homogenizer in 5 ml medium, and homogenized to a smooth consistency. Brain homogenates were transferred to conical tubes on ice and adjusted to a 7-ml volume, and 3 ml Percoll (Sigma-Aldrich) was added to yield a final 30% Percoll concentration. This was underlayed with 70% Percoll and centrifuged at 2500 rpm. The interface was removed and washed, RBCs were lysed, and cells were stained with anti-CD8 and MHC class I tetramers DbNP396–404 and Dbgp33–41.
IFN-
ELISPOT assays
Allospecific T cell responses were measured by IFN- ELISPOT
assay using splenocytes or Histopaque separated (Sigma-Aldrich)
peripheral blood leukocytes obtained from skin-grafted
CD43+/+ or CD43-/- mice.
The capture Ab for this assay, rat anti-mouse IFN- (clone
R4-6A2; BD PharMingen), was incubated at 4 µg/ml in PBS (100
µl/well) at 4°C overnight in ester cellulose-bottom 96-well plates
(Millipore, Bedford, MA). After washing with PBS, 3-fold serial
dilutions of responding cells were added. A total of 5 x
105 irradiated donor splenocytes (BALB/c) were
added to each well and plates were incubated overnight at 37°C. After
the culture period, cells were removed by washing the plates with
PBS-Tween (0.05%). Biotinylated anti-mouse IFN- (clone XMG1.2;
BD PharMingen) was added at 4 µg/ml (100 µl/well) for 2 h,
plates were washed, and HRP-avidin D (Vector Laboratories) was added
for 1 h. Following a final wash, spots were developed with the
substrate 3-amino-9-ethyl-carbazole (Sigma-Aldrich) with 0.015%
H2O2, allowed to air dry,
and quantitated.
BrdU incorporation
Mice were fed BrdU (Sigma-Aldrich) at 1 mg/ml in their drinking water, changed daily, for days 8–15 following LCMV-Armstrong challenge i.p. On day 15 mice were sacrificed and peripheral blood and spleen were harvested. After perfusion with 5 ml cold PBS, liver was harvested. PBMCs were isolated as previously described (1). Lymphocytes from the liver were obtained after passage through a mesh screen. Cell suspensions were incubated at 37°C for 1 h with a 10x stock of 2.5 mg/ml collagenase B and 0.29 mg/ml DNase I in PBS. Large tissue debris was discarded and cells were resuspended in 44% Percoll, underlayed with 56% Percoll, and spun for 20 min at 2000 rpm in an IEC centrifuge (IEC, Needham Heights, MA). After isolation from the Percoll gradient, RBCs were lysed and cell yield was determined. Cell surface staining with MHC class I tetramers specific for DbNP396–404 and anti-CD8-PE followed by intracellular staining for BrdU incorporation as per the manufacturer’s instructions (BrdU Flow kit; BD PharMingen). Briefly, cells were permeabilized with Cytofix/Cytoperm and treated with DNase to expose incorporated BrdU, followed by staining with anti-BrdU-FITC.
In vitro apoptosis assay
Splenocytes were harvested from infected mice on days 8, 10, or 12 and 1 x 106 cells were cultured for 16 h in 96-well flat-bottom plates at 37°C. Cells were transferred to a 96-well U-bottom plate for staining. Following surface staining with MHC class I tetramers and anti-CD8 Abs, cells were washed and incubated with annexin V staining buffer (10 mM HEPES/NaOH (pH 7.4), 140 mM NaCl, 2.5 mM CaCl2) with a 1/20 dilution of annexin V-FITC and a 1/5 dilution of 7-AAD (BD PharMingen) for 15 min at room temperature. Cells were washed and immediately assayed by flow cytometry.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD43-deficient mice show normal T and B cell development and have
similar numbers of T lymphocytes in the periphery (8, 18).
Wild-type or CD43-deficient mice were infected i.p. with 2 x
105 PFU of the Armstrong strain of LCMV, and mice
were sacrificed 8 or 65 days postinfection. Splenocytes and lymph node
T cells were stained with Abs to CD8, S7, or 1B11 and MHC class I
tetramers specific for the dominant epitopes
Dbgp33–41 or
DbNP396–404
(1). Data from spleen cells are shown, but similar results
were obtained from lymph node cells. Similar percentages of Ag-specific
CD8 T cells were obtained from both genotypes (Fig. 1
A).
|
B). However, binding by 1B11 changes dramatically in
CD43+/+ mice; 1B11 binding is low on naive CD8 T
cells, dramatically increased on virus-specific effector CD8 T cells,
and reduced on virus-specific memory CD8 T cells (Fig. 1B).
Double staining of +/+ effector CD8 T cells with 1B11 and S7 reveals
binding of both Abs on the same cells. Binding by mAbs S7 and 1B11 on T
cells from wild-type mice is summarized in Table I.
|
B). Other surface markers such as CD44 and L-selectin were
unaffected and similar surface expression was observed between +/+ and
-/- effector CD8 T cells (Ref. 9 and data not shown).
These data demonstrate that the increased 1B11 binding on CD8 effector
T cells requires the expression of CD43. Reduced binding of PNA on effector and memory T cells in CD43-/- mice
We have previously demonstrated that virus-specific T cells become
PNAhigh, and this increased PNA reactivity may
result from increased neuraminidase activity in activated T cells
(2). Alterations in expression or activity of one or more
sialyltransferases could also affect PNA binding (19, 20).
We examined PNA binding on T cells derived from
CD43-/- mice after challenge with LCMV.
Effector and memory cells were gated for expression of CD8 and
DbNP396–404, while naive
cells were gated on CD44low CD8 T cells from
uninfected mice. While PNA binding to effector T cells was markedly
up-regulated compared with naive cells from both +/+ and -/- mice,
the level of binding to effector and memory -/- CD8 T cells was
significantly reduced compared with similar populations of +/+ cells
(
30–40%) (Fig. 1C). While prior work has demonstrated
that CD43 is a PNA-binding glycoprotein on thymocytes
(21), the data presented in this work demonstrate that
CD43 expression contributes to PNA binding by activated peripheral T
cells. This suggests that the glycosylation status of CD43 on
peripheral T cells is dynamically regulated during a viral infection in
vivo. Because PNA binding to peripheral T cells is reduced but not
abolished in the CD43-/- mice, expression of
other O-glycosylated proteins such as CD8 most likely
contribute to PNA binding (21, 22, 23).
Modest role for CD43 in costimulation in vivo
Cross-linking CD43 has been shown to play a role in the
costimulation of T cells in vitro (12); however,
CD43-/- T cells have been shown to be
hyperproliferative in vitro (8, 13). We examined the CD8 T
cell response on day 8 in CD43-/- mice after
acute infection with LCMV. Wild-type mice show the peak of expansion
approximately day 8 postinfection. While
CD43-/- mice show similar percentages of
virus-specific CD8 T cells (Fig. 1), the total cell number is slightly
reduced, accounting for an 1.5- to 2-fold reduction in the numbers
of virus-specific T cells in CD43-/- mice (Fig. 2, A and B). Both
groups of mice show undetectable virus titers in day-8 serum, liver,
kidney, and spleen (data not shown). CTL-specific lysis was measured,
as well as intracellular cytokine production, and no differences were
seen in CD43-/- mice, even when data were
normalized for CD8 T cell numbers (Fig. 2C and data not
shown). CD8 T cells specific to subdominant epitopes
Dbgp276–306 and
KbNP205–212 were also
reduced in magnitude in CD43-/- compared with
CD43+/+ mice (Fig. 2D). These results
demonstrate a modest effect in the expansion of naive CD8 T cells,
supporting a role in costimulation. However, this slight decrease in
expansion has little overall effect on the acute immune response, as
viral clearance is unaffected.
|
CD43 has been shown to play a role in the trafficking of T cells
and monocytes to sites of inflammation (10, 11). However,
it is also purported to play an antiadhesive role in lymphocyte
trafficking, suggesting increased trafficking of lymphocytes to some
tissues in the absence of CD43 (9). We examined the role
of CD43 in trafficking of CD8 T cells to the brain of i.c. infected
mice. In this model, infiltration of LCMV-specific CD8 T cells to the
meninges of i.c. infected mice results in mortality, and the onset of
symptoms leading to mortality is rapid and acute (reviewed in Ref.
24). CD43+/+ or
CD43-/- mice were infected with 1 x
102 or 1 x 105 PFU
LCMV-Armstrong i.c. and survival was examined. Although both +/+ and
-/- mice demonstrated 100% mortality regardless of the dose used,
CD43-/- mice showed a delay in the onset of
mortality at both high and low viral doses (Fig. 3A and data not shown). These
results suggested that, while functional, the
CD43-/- CD8 T cells may be defective in their
ability to traffic to the brain.
|
B). By comparing
CD44high CD8 T cells in the spleen and the brain
as a ratio, we saw that this difference in activated CD8 T cells in the
brain exceeds the difference seen in the spleen and suggests this
difference is more than that seen from costimulation only (data not
shown). Immunohistochemistry of brain sections confirmed that
CD43-/- mice had reduced CD8 T cell infiltrates
in the leptomeninges (Fig. 3, C and D), as well
as choroid plexus and ventricular ependyma. These results suggest that
CD43 plays a significant role in the trafficking of CD8 T cells to the
CNS. Additionally, it supports previously published work using Ab
blockade of CD43 to prevent T cell infiltration to inflamed pancreatic
islets and salivary and lacrimal glands of nonobese diabetic mice
(10, 25). However, this defect in trafficking appears to
be tissue specific, as we saw no defect in trafficking of T cells to
the liver of infected CD43-/- mice (as shown
later). Furthermore, CD43-/- mice
rejected skin allografts at days 10–13, similar to
CD43+/+ mice, suggesting no defect in trafficking
of CD43-/- T cells to skin. Thus, different
tissues may have different CD43-dependent mechanisms of T cell
migration during immune responses. CD43 plays a negative regulatory role in the down-modulation of the immune response
When we examined the kinetics of the immune response in
CD43-/- mice we saw a modest role in the
expansion phase of the response but, surprisingly, a significant delay
in the down-modulation or waning of the response (Fig. 4). Days 8–15 following LCMV challenge
are characterized by a precipitous loss in the numbers of Ag-specific T
cells, usually resulting in an 10-fold reduction of Ag-specific T
cells (26, 27). On day 15 postinfection,
CD43-/- mice showed consistently higher numbers
of activated CD8 T cells, demonstrating only an 2-fold reduction in
Ag-specific T cells, suggesting a defect in the death or increased
proliferation of these cells (Fig. 4).
|
). However, they
had slightly reduced numbers of allospecific T cell responses
(1.7-fold) at the peak of the response (day 12), showing that, similar
to the viral infection data, there is a modest effect on the generation
of the T cell response (Fig. 5). During the contraction phase, by day
16, CD43-/- mice showed increased allospecific
T cell numbers relative to wild-type mice (Fig. 5). Taken together with
the acute LCMV response, the absence of CD43 resulted in a delay in the
waning or contraction of the T cell response, resulting in longer
persistence of Ag-specific T cells in vivo.
|
To determine whether this increase in numbers of activated T cells
during the contraction phase was due to increased proliferation of
-/- T cells, CD43+/+ or
CD43-/- mice were infected with LCMV-Armstrong,
and on days 8–15 postinfection they were given BrdU in their drinking
water. On day 15 postinfection, mice were sacrificed and BrdU
incorporation was examined in CD8 T cells from the spleen, liver, and
PBMC. CD43-/- virus-specific CD8 T cells showed
no increased BrdU incorporation in any of the tissue compartments
examined, suggesting no increased proliferation during the contraction
phase, even though increased numbers of Ag-specific CD8 T cells were
observed (Fig. 6). These data argue
against increased proliferation of CD43-/- CD8
T cells during the contraction phase. However, the defect in the
contraction phase is not permanent, as immune mice at days 50 and 65
show similar numbers of Ag-specific CD8 T cells (Fig. 4). Rather, it is
a transient defect or delay.
|
We examined whether this delay in the contraction phase was due to
decreased death, because we saw no evidence of increased proliferation.
We examined bcl-2 levels in Ag-specific effector CD8 T cells from
CD43-/- mice. Bcl-2 has been characterized as
an antiapoptotic protein and its overexpression has been found to
increase resistance to apoptosis (29). Following viral
infection, bcl-2 expression has been found to decrease on effector
cells compared with naive T cells and then increase again on memory T
cells to higher levels than on naive (27, 30).
CD43-/- effector virus-specific T cells showed
increased levels of bcl-2 compared with CD43+/+
(Fig. 7). However, directly ex vivo, we
saw similar percentages (3–6%) of apoptotic Ag-specific CD8 T cells
by Annexin V and 7-AAD at day 8, 10, or 12 (data not shown). Because
apoptotic cell uptake is very efficient in vivo, we examined death of
effector Ag-specific CD8 T cells from +/+ or -/- mice after in vitro
culture. Culturing of an equal number of spleen cells overnight
revealed 2- to 3-fold increased percentages of Annexin
V+7-AAD+ cells in +/+ vs
-/- effector CD8 T cells (Fig. 7). Taken together with our results
showing no increased BrdU incorporation of -/- CD8 T cells,
these results suggest that the increased numbers of Ag-specific CD8 T
cells during the contraction phase of an immune response in
CD43-/- mice is most likely the result of a
defect in apoptosis of effector CD8 T cells. These data would support
studies suggesting a role for CD43 in apoptosis of leukocytes
(31, 32).
|
We examined chronic infection in CD43+/+ vs
CD43-/- mice using a persistent strain of LCMV,
clone 13. Because the virus is not cytopathic, LCMV is a classic model
of immunopathology. Tissue damage that occurs following infection is
entirely dependent on the immune response (reviewed in Ref.
24). Previous reports have suggested that functional
inactivation or down-modulation of immune responses during chronic
infection are critical for host survival (33, 34, 35). When
previously uninfected adult mice are infected with LCMV clone 13
i.v., the virus replicates and disseminates rapidly (36).
It can persist in the serum for up to 100 days, and remains
indefinitely in some tissues. When CD43-/- mice
were infected with LCMV clone 13 they showed similar Ag-specific
responses in spleen, liver, and PBMC compartments at day 8 (Fig. 8A). Furthermore, day 8
postinfection viral titers in the serum of +/+ and -/- mice are
comparable (Fig. 8B). However,
CD43-/- mice showed dramatically increased
disease following day 7 postinfection and increased mortality relative
to wild-type mice (Fig. 8C). Together with the data from
acute infection showing persistence of activated CD8 T cells during the
contraction phase in vivo, these data support a negative regulatory
role of CD43 on activated CD8 T cells. During chronic viral infection,
CD43 appears to play a critical negative regulatory role during
down-modulation, and in its absence immunopathology may result, causing
increased mortality. These results argue for a very dynamic role
of the CD43 glycoprotein during an immune response reflective of the
dynamic modification through the expression and glycosylation it
undergoes during an immune response. On naive T cells it may play a
more positive regulatory role in costimulation and trafficking, while
on effector T cells it may play a more negative regulatory role in
mediating the death of effector T cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The exact role of CD43 has not been well defined, due to its seemingly contradictory roles in several processes such as cell adhesion and costimulation. We propose that, depending on the state of activation of the T cell, CD43 may have positive or negative regulatory roles during an immune response. On a naive T cell, the 115-kDa glycoform is abundantly sialylated, and this large negatively charged glycoprotein seems to play a negative regulatory role in T cell homing (9) and activation in vitro (8). However, our work suggests that, on activated T cells, CD43 and other cell surface glycoproteins become hyposialylated. This reduction in sialic acid content could result in reduced binding to endogenous lectins such as the recently described CD43 counterreceptor Siglec-1 (37), a sialic acid-binding lectin, and enhanced binding to lectins such as MMGL (38) and galectin-1 (39) that recognize terminal galactose residues on cell surface glycoproteins. Thus, depending on the type of ligand/receptor interactions being studied, differential glycosylation of CD43 could control the type or magnitude of specific T cell interactions.
Interestingly, CD43 expression as assayed by S7 binding is differentially regulated on CD4 vs CD8 T cells. CD8 T cells show constitutive S7 binding on both CD44high and CD44low CD8 T cells, while CD4 T cells show S7 binding on CD44high but not CD44low T cells (40). However, CD4 T cells and CD8 T cells show increased binding of 1B11 on CD44high cells. This differential expression of CD43 may play a role in differential activation and clearance rates of CD8 T cells and CD4 T cells (41).
Our finding showing no increase in 1B11 binding of CD43-/- effector CD8 T cells in vivo extends previous work noting low-level binding to thymocytes and Con A blasts of CD43-/- mice (7). This group saw 1B11 reactivity in CD43-/- mice on a subset of lymph node cells and noted low-level binding to a small population of CD8 splenocytes in CD43-/- mice as data not shown. They suggested this 1B11 reactivity was binding an epitope on CD45RB that is independent of core 2 O-glycans. Importantly, they clearly state this binding on blasts and thymocytes is much less than 1B11 binding on wild-type cells, which agrees with our work on Ag-specific CD8 T cells. Our data show clearly that on virus-specific effector and memory CD8 T cells generated after an in vivo challenge the up-regulated binding of 1B11 is dependent on CD43 expression.
Mortality in mice following LCMV infection i.c. has been shown to be critically dependent on functional CD8 T cell infiltration of the brain (reviewed in Ref. 24). We show that CD43-/- mice infected with LCMV-Armstrong i.c. show a delay in mortality, and this delay is consistent with our findings showing reduced numbers of CD8 T cell infiltrates in the CNS of these mice. These results are suggestive of a defect in CD8 T cell trafficking to the CNS, but they do not rule out alternative mechanisms. One report examining CD43 expression in brain tissue of normal and Alzheimer’s disease cases demonstrated the expression of CD43 on human microglia (42). It is possible that the reduction in CD8 T cell numbers in the CNS of CD43-/- mice could be secondary to a defect in microglial cells. Thus, the contribution of other cell types to the defect seen in these mice remains to be determined.
Recent cross-linking studies have suggested that T cell activation through CD43 leads to vav tyrosine phosphorylation and induces Cbl-serine phosphorylation (4, 43). Cbl and cbl-b have been shown to negatively regulate T cell activation (44, 45, 46). Interestingly, Wiskott-Aldrich syndrome protein (WASp) is purported to be a downstream signaling target of the cbl-b signaling cascade (44). CD43 was earlier characterized because of its disrupted expression/glycosylation on leukocytes from patients suffering from the X-linked immunodeficiency Wiskott-Aldrich syndrome (47, 48). It has been demonstrated that mutation(s) in WASp is the causative mutation for this disease (49). T cells from WASp-/- mice fail to form effective TCR caps, resulting in defects in signaling through the TCR (50). Recent work has shown that CD43 is excluded from the TCR-APC synapse and that this movement of CD43 away from the synapse is mediated by ezrin-radixin-moesin-dependent mechanisms (14, 15, 16, 17). Thus, the disregulation of CD43 in patients with Wiskott-Aldrich syndrome may serve as some sort of compensatory mechanism in T cell activation in these patients due to cytoskeleton considerations. Future studies will aim at examining TCR signaling in Ag-specific effector and memory CD43+/+ and CD43-/- CD8 T cells.
Finally, it is interesting to note that the high-molecular mass glycoform of CD43 remains high on T cells during chronic infection in both mice (T. Onami and R. Ahmed, unpublished data) and humans (51). During the course of an acute infection, CD43 on activated T cells seems to serve to regulate the numbers of activated T cells that remain during the waning of the response. Perhaps during a chronic infection CD43 may serve to regulate numbers and/or responsiveness of the T cell to persisting Ag. Future studies will examine these questions in more detail.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Rafi Ahmed, Emory Vaccine Center and Department of Microbiology and Immunology, Emory School of Medicine, 1510 Clifton Road, Room G211, Atlanta, GA 30322. E-mail address: ra{at}microbio.emory.edu
3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; PNA, peanut agglutinin; BrdU, bromodeoxyuridine; 7-AAD, 7-amino actinomycin D; i.c., intracranial(ly); WASp, Wiskott-Aldrich syndrome protein.
Received for publication October 12, 2001. Accepted for publication April 9, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2,6-sialyltransferase induced early after lymphocyte activation. Int. Immunol. 11:731. coreceptor stalk modulates ligand binding. Cell 107:501.[Medline]
This article has been cited by other articles:
|
|
 |
|
  J. D. Brien, J. L. Uhrlaub, A. Hirsch, C. A. Wiley, and J. Nikolich-Zugich Key role of T cell defects in age-related vulnerability to West Nile virus J. Exp. Med., November 9, 2009; (2009) jem.20090222v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. D. Liu, T. Tomassian, K. W. Bruhn, J. F. Miller, F. Poirier, and M. C. Miceli Galectin-1 Tunes TCR Binding and Signal Transduction to Regulate CD8 Burst Size J. Immunol., May 1, 2009; 182(9): 5283 - 5295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zeng, H. M. Joo, B. Rajini, J. P. Wrammert, M. Y. Sangster, and T. M. Onami The Generation of Influenza-Specific Humoral Responses Is Impaired in ST6Gal I-Deficient Mice J. Immunol., April 15, 2009; 182(8): 4721 - 4727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Cannon, A. Collins, P. D. Mody, D. Balachandran, K. J. Henriksen, C. E. Smith, J. Tong, B. S. Clay, S. D. Miller, and A. I. Sperling CD43 Regulates Th2 Differentiation and Inflammation J. Immunol., June 1, 2008; 180(11): 7385 - 7393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Suvas, H. M. Dech, F. Sambira, J. Zeng, and T. M. Onami Systemic and Mucosal Infection Program Protective Memory CD8 T Cells in the Vaginal Mucosa J. Immunol., December 15, 2007; 179(12): 8122 - 8127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. D. Mody, J. L. Cannon, H. S. Bandukwala, K. M. Blaine, A. B. Schilling, K. Swier, and A. I. Sperling Signaling through CD43 regulates CD4 T-cell trafficking Blood, October 15, 2007; 110(8): 2974 - 2982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hikono, J. E. Kohlmeier, S. Takamura, S. T. Wittmer, A. D. Roberts, and D. L. Woodland Activation phenotype, rather than central- or effector-memory phenotype, predicts the recall efficacy of memory CD8+ T cells J. Exp. Med., July 9, 2007; 204(7): 1625 - 1636. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Cush, K. M. Anderson, D. H. Ravneberg, J. L. Weslow-Schmidt, and E. Flano Memory Generation and Maintenance of CD8+ T Cell Function during Viral Persistence J. Immunol., July 1, 2007; 179(1): 141 - 153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Matsumoto, A. Shigeta, Y. Furukawa, T. Tanaka, M. Miyasaka, and T. Hirata CD43 Collaborates with P-Selectin Glycoprotein Ligand-1 to Mediate E-Selectin-Dependent T Cell Migration into Inflamed Skin J. Immunol., February 15, 2007; 178(4): 2499 - 2506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Van Dyken, R. S. Green, and J. D. Marth Structural and Mechanistic Features of Protein O Glycosylation Linked to CD8+ T-Cell Apoptosis Mol. Cell. Biol., February 1, 2007; 27(3): 1096 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Baron, M.-C. Meunier, E. Caron, C. Cote, M. J. Cameron, D. J. Kelvin, R. LeBlanc, V. Rineau, and C. Perreault Asynchronous Differentiation of CD8 T Cells That Recognize Dominant and Cryptic Antigens J. Immunol., December 15, 2006; 177(12): 8466 - 8475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Carlow and H. J. Ziltener CD43 Deficiency Has No Impact in Competitive In Vivo Assays of Neutrophil or Activated T Cell Recruitment Efficiency J. Immunol., November 1, 2006; 177(9): 6450 - 6459. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Hernandez, J. T. Nguyen, J. He, W. Wang, B. Ardman, J. M. Green, M. Fukuda, and L. G. Baum Galectin-1 Binds Different CD43 Glycoforms to Cluster CD43 and Regulate T Cell Death J. Immunol., October 15, 2006; 177(8): 5328 - 5336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ryan and T. D. Schell Accumulation of CD8+ T Cells in Advanced-Stage Tumors and Delay of Disease Progression following Secondary Immunization against an Immunorecessive Epitope J. Immunol., July 1, 2006; 177(1): 255 - 267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Fuhlbrigge, S. L. King, R. Sackstein, and T. S. Kupper CD43 is a ligand for E-selectin on CLA+ human T cells Blood, February 15, 2006; 107(4): 1421 - 1426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Randhawa, H. J. Ziltener, J. S. Merzaban, and R. W. Stokes CD43 Is Required for Optimal Growth Inhibition of Mycobacterium tuberculosis in Macrophages and in Mice J. Immunol., August 1, 2005; 175(3): 1805 - 1812. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Chen, N. Khanna, S. A. Stohlman, and C. C. Bergmann Virus-Specific and Bystander CD8 T Cells Recruited during Virus-Induced Encephalomyelitis J. Virol., April 15, 2005; 79(8): 4700 - 4708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Martin and R. L. Tarleton Antigen-Specific T Cells Maintain an Effector Memory Phenotype during Persistent Trypanosoma cruzi Infection J. Immunol., February 1, 2005; 174(3): 1594 - 1601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ramakrishna, S. A. Stohlman, R. A. Atkinson, D. R. Hinton, and C. C. Bergmann Differential Regulation of Primary and Secondary CD8+ T Cells in the Central Nervous System J. Immunol., November 15, 2004; 173(10): 6265 - 6273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-C. Wang, D. Montufar-Solis, B.-B. Teng, and J. R. Klein Maximum Immunobioactivity of Murine Small Intestinal Intraepithelial Lymphocytes Resides in a Subpopulation of CD43+ T Cells J. Immunol., November 15, 2004; 173(10): 6294 - 6302. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Z. Wang, M. A. Brehm, and R. M. Welsh Preapoptotic Phenotype of Viral Epitope-Specific CD8 T Cells Precludes Memory Development and Is an Intrinsic Property of the Epitope J. Immunol., October 15, 2004; 173(8): 5138 - 5147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kyoizumi, T. Ohara, Y. Kusunoki, T. Hayashi, K. Koyama, and N. Tsuyama Expression Characteristics and Stimulatory Functions of CD43 in Human CD4+ Memory T Cells: Analysis Using a Monoclonal Antibody to CD43 That Has a Novel Lineage Specificity J. Immunol., June 15, 2004; 172(12): 7246 - 7253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tong, E. J. Allenspach, S. M. Takahashi, P. D. Mody, C. Park, J. K. Burkhardt, and A. I. Sperling CD43 Regulation of T Cell Activation Is Not through Steric Inhibition of T Cell-APC Interactions but through an Intracellular Mechanism J. Exp. Med., May 3, 2004; 199(9): 1277 - 1283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhou, R. Ou, L. Huang, G. E. Price, and D. Moskophidis Differential Tissue-Specific Regulation of Antiviral CD8+ T-Cell Immune Responses during Chronic Viral Infection J. Virol., April 1, 2004; 78(7): 3578 - 3600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Ford, T. M. Onami, A. I. Sperling, R. Ahmed, and B. D. Evavold CD43 Modulates Severity and Onset of Experimental Autoimmune Encephalomyelitis J. Immunol., December 15, 2003; 171(12): 6527 - 6533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. v. d. Most, K. Murali-Krishna, and R. Ahmed Prolonged presence of effector-memory CD8 T cells in the central nervous system after dengue virus encephalitis Int. Immunol., January 1, 2003; 15(1): 119 - 125. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) and CD43-/- mice (
)
received H-2d skin allografts and skin graft survival was
measured. Both CD43+/+ and CD43-/- mice
rejected grafts with similar kinetics between days 10 and 13. On days
12 (B) and 16 (C) after receiving grafts,
allospecific responses were measured by IFN-
