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Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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45 nm (3). It is abundantly O-glycosylated and bears
numerous sialic acid residues (4, 5). These structural features have
been thought to account for the negative regulatory properties of CD43.
Specifically, the combination of large size and negative charge has led
to the model that CD43 sterically interferes with cell-cell contact in
a nonspecific manner. However, this model fails to account for any
potential function of the cytoplasmic domain of CD43. Cross-linking of CD43 on the surface of T cells has been shown to synergize with TCR engagement in the induction of a proliferative response (6, 7, 8). In addition, CD43 engagement may lead to regulation of both integrin- and nonintegrin-mediated adhesion (9, 10, 11). CD43 may also be important in the regulation of cell survival (12, 13, 14, 15, 16). Recent work with CD43 on human T cells has demonstrated that ligation of CD43 with the mAb L10 resulted in phosphorylation of Shc and induced the formation of a Shc/Grb2 complex as well as the tyrosine phosphorylation of Vav and mitogen-activated protein kinase activation (17). In addition, the cytoplasmic tail of CD43 has been demonstrated to interact with the cytoskeletal linker proteins Ezrin and Moesin (18, 19). Other studies have suggested an interaction of CD43 with the protein tyrosine kinase Fyn (20). These and other observations have suggested that CD43 may have signaling properties.
Given the conflicting data as to how CD43 regulates cell adhesion and activation, we examined the structural elements of CD43 responsible for modulating the adhesive and proliferative properties of T cells. Using both cell lines and primary cells deficient in CD43 expression, we demonstrate that the cytoplasmic domain of CD43 is both necessary and sufficient for the antiadhesive effect of CD43. In addition, the cytoplasmic domain is required for the inhibitory effect of CD43 on T cell proliferation. Surprisingly, however, the cytoplasmic tail of CD43 is dispensable for the costimulatory effect of coligation of CD43 with TCR engagement. These data suggest that the antiadhesive and antiproliferative effects of CD43 are not mediated exclusively by steric interactions of the extracellular domain. The requirement for the cytoplasmic tail in this circumstance may reflect a direct signaling role for CD43, or alternatively may mediate critical interactions with the cytoskeleton.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD43-deficient mice (1) (generously provided by Dr. Blair Ardman, New England Medical Center, Boston, MA) were backbred for six generations onto the C57BL/6 background and housed in specific pathogen-free conditions at Washington University School of Medicine (St. Louis, MO). Wild-type (wt)3 C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME).
Antibodies
Anti-CD43 mAb R2/60 (rat IgM) was purified from ascites by
affinity chromatography using an Immunopure mannan binding protein
(MBP) column (Pierce, Rockford, IL). FITC and
phycoerythrin-conjugated control or anti-CD43 (clone S7, rat IgG)
Abs were purchased from PharMingen (San Diego, CA). Anti-IFN-
R
-chain mAb (GIR 94, mouse IgG) was provided by Dr. R. Schreiber
(Washington University). FITC-conjugated anti-rat IgM was purchased
from Kirkegaard and Perry Laboratories (Gaithersburg, MD), and
FITC-conjugated anti-mouse IgG was obtained from Sigma (St. Louis,
MO). Anti-CD3 mAb (2C11) was generously provided by Dr. J. A.
Bluestone (University of Chicago, Chicago, IL). Anti-CD28 mAb (PV-1,
hamster IgG) was provided by Dr. Carl June (Naval Medical Research
Institute, Bethesda, MD).
Cell aggregation assays
cDNA constructs encoding for either full-length murine CD43,
murine CD43 in which all but three amino acids of the cytoplasmic tail
had been deleted, or chimeric proteins in which the extracellular
domain of the human IFN-R -chain or of mouse CD8 was fused to the
transmembrane and intracellular domain of CD43 (IFN-R cDNA was
generously provided by R. Schreiber, Washington University; murine CD8
cDNA was provided by M. Thomas, Washington University) were subcloned
into the expression vector pBabe (21), which allows for selection of
stable clones based upon resistance to puromycin. The human T cell line
CEM deficient in expression of CD43 (Ref. 22 , provided by Dr.
B. Ardman, New England Medical Center, Boston, MA) was transfected with
each construct or empty vector alone by electroporation; stable
transfectants were selected for in the presence of puromycin (0.75
µg/ml; Sigma). Puromycin-resistant cells were cloned by limiting
dilution and screened for protein expression by flow-cytometric
analysis using anti-CD43 mAb (R2/60 (8), anti-IFN-R mAb, or
anti-CD8 (PharMingen)). Samples were analyzed on a FACScalibur flow
cytometer using CellQuest software (Becton Dickinson, Mountain View,
CA).
The parental wt, CD43-deficient, or transfected CEM cells were stimulated with 100 ng/ml PMA (Sigma) at a density of 1 x 106 cells/ml in media (RPMI 1640 supplemented with 2 mM L-glutamine, 10 mM HEPES, 100 U/ml penicillin, and 100 µg/ml streptomycin (Life Technologies, Gaithersburg, MD)). A total of 2 ml of the stimulated cells were placed in each well of a six-well tissue culture dish that had been preblocked for 2 h with casein blocking reagent (Pierce). The cells were maintained at 37°C and 5% CO2 for 3 h and then assayed for homotypic aggregation. The percentage of aggregated cells was determined for each condition by carefully removing 100 µl of cells through a pipet in which the tip had been cut to enlarge the opening. A total of 10 µl of the sample was placed immediately into one side of a hemocytometer, and the remaining sample was mixed in an Eppendorf tube to disrupt cellular aggregates. The total number of free cells (those not in an aggregate of any size) was determined for the unmixed sample by counting all individual cells in four squares of the hemocytometer. The total number of cells present was then determined by counting the total number of cells in the same area of the hemocytometer after mixing of the sample. The percentage of aggregated cells was then calculated by the formula (number of free cells/number of total cells) x 100. Three independent measurements were obtained for each sample, and the mean ± SD of the three measurements was shown. Each assay has been performed a minimum of three times, with at least two independent clones and one representative experiment presented. Representative fields were photographed at x200 magnification with a Leitz inverted microscope.
Retroviral infection
The retroviral expression vector GFP-RV (23) was generously provided by Dr. W. Sha (University of California, Berkeley, CA). The full-length or mutant murine CD43 cDNA constructs were subcloned into the XhoI site of the vector or a control vector that expresses a tailless form of human CD4 (provided by Dr. Kenneth Murphy, Washington University). A total of 20 µg of DNA was used to transfect a 100-mm dish of the Phoenix E packaging cell line (provided by Dr. Garry Nolan, Stanford University, Stanford, CA) by chloroquine-mediated calcium phosphate transfection. At 48 h posttransfection, the retroviral supernatant was harvested and used to infect lymph node cells from wt or CD43-deficient mice that had been activated 48 h previously with PMA (5 ng/ml) plus ionomycin (0.1 µg/ml) to facilitate infection. The cells were cocultured with the retroviral supernatant for 72 h and then sorted. Cells expressing the retrovirally encoded protein were sorted by immunomagnetic sorting using CD43 microbeads and a VarioMacs magnetic sorter (Miltenyi Biotec, Auburn, CA). Control cells expressing tailless human CD4 were sorted with CD4 microbeads. Following sorting, the cells were washed and rested overnight in fresh media before stimulation. The purity of the sort was assessed by flow cytometric analysis and was routinely >90%.
Proliferation assays
Wild-type or CD43-deficient T cells transduced with either control, full-length, or mutant CD43 were plated at 5 x 104 cells/well in 96-well microtiter plates and stimulated with soluble anti-CD3 mAb (0.1 µg/ml). Proliferation was determined by pulsing with 1.0 µCi tritiated thymidine ([3H]TdR; ICN, Costa Mesa, CA) for the final 12 h of a 36-h culture. For assays of CD43 costimulation, cells were cultured in round-bottom 96-well plates and stimulated with plate-immobilized anti-CD3 (0.1 µg/ml) alone or in conjunction with immobilized anti-CD43 (mAb R2/60, 1 µg/ml) or soluble anti-CD28 (PV-1, 1 µg/ml). All proliferation assays were performed in triplicate. Data shown are the mean ± SD of triplicate wells. All plates were harvested onto glass microfiber filtermats using a Skatron 96-well plate harvester and counted on a Wallac 1205 betaplate liquid scintillation counter (Turku, Finland).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been thought that the antiadhesive effect of CD43 is
mediated primarily by the large size and negative charge of the
extracellular domain. To examine this, we tested the structural domains
of CD43 for their ability to inhibit cell-cell interactions. A
CD43-deficient human T cell line, CEM cells, had been generated
previously by gene targeting and shown to have increased homotypic
adhesion in response to PMA stimulation (22). We introduced into this
cell line murine CD43 either as a full-length protein (FL CD43), with
the cytoplasmic tail deleted (CD43
cyto) or a chimeric protein in
which the extracellular domain of the human IFN-R -chain
(IFN-/CD43) or of murine CD8 (CD8/CD43) was fused to the
transmembrane and intracellular domain of CD43. Clones were selected
that had similar levels of expression of each construct, as assessed by
flow cytometry (Fig. 1
). The cells were then tested for
homotypic adhesion following stimulation with PMA. A quantitative
assessment of cellular aggregation (Fig. 2A)
demonstrated that the wt (CD43+/+) cell line had low levels
of homotypic adhesion following stimulation, whereas the majority of
the CD43-deficient cells (CD43-/-) were in large
aggregates. Expression of the full-length murine CD43 protein restored
the wt phenotype, with low levels of homotypic adhesion, whereas cells
that express mutant CD43 lacking the cytoplasmic domain had high levels
of aggregation, similar to the CD43-/- cells. Microscopic
examination of the cells confirmed that the majority of cells
expressing full-length CD43 were either not in aggregates or were in
small clumps (Fig. 3, A and C). In
contrast, cells lacking CD43 expression or expressing the cytoplasmic
deletion mutant of CD43 formed very large aggregates, with the majority
of the cells being in aggregates (Fig. 3, B, D,
and F). Thus, the cytoplasmic domain is required for the
CD43 to inhibit homotypic interactions. Flow-cytometric analysis showed
no change in CD43 expression following stimulation with PMA, suggesting
that shedding of CD43 is not responsible for the increased adhesion
(data not shown).
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/CD43
protein altered homotypic aggregation. Both full-length CD43 as well as
the chimeric protein inhibited PMA-induced homotypic adhesion (Fig. 2
B). Similar to the wt CD43+/+ CEM cells, the
clones expressing full-length CD43 or the chimeric protein were in very
small aggregates or remained as single cells (Fig. 3, A,
C, and E). To be certain that the restoration of
the wt phenotype was not a function of the IFN- extracellular
domain, we examined a second chimera. Wild-type CEM cells express human
CD4 and lack CD8 expression. Expression of a fusion protein of the
murine CD8 extracellular domain to CD43 transmembrane and intracellular
domain also inhibited PMA-induced aggregation (Fig. 2C).
Similar to wt, microscopic examination revealed that these cells were
in only small aggregates or remained as single cells (data not shown).
These data suggest that the cytoplasmic domain of CD43 is both
necessary and sufficient to inhibit cell-cell contact in this system. Negative regulation of T cell proliferation by CD43 requires the intracellular domain
T cells from CD43-deficient mice have been shown to have an
increased proliferative response to stimulation through the TCR (1, 2).
The mechanism for this effect has not been elucidated definitively, but
has been thought to be due to the increased adhesive properties of
CD43-deficient cells. This in turn has been presumed to be due to the
lack of the bulky extracellular domain of CD43. To test this model, we
examined the structural requirements for the antiproliferative effect
of CD43 on primary murine T cells. Lymph node cells were isolated from
CD43-deficient mice and activated with PMA and ionomycin to facilitate
retroviral infection. The T cells were then cultured with retrovirus
encoding either full-length murine CD43, CD43cyto construct, or a
control vector encoding for tailless human CD4. After 72 h, the
cells were sorted by immunomagnetic selection, washed, and rested
overnight in fresh medium. Expression of CD43 was confirmed by flow
cytometry (Fig. 4). Sorting efficiencies were routinely
90% (data not shown). The T cells were then stimulated with
anti-CD3 (0.1 µg/ml), and proliferation was determined by
[3H]TdR incorporation (Fig. 5). T cells
from CD43-deficient T cells infected with control retrovirus had an
increased proliferative response as compared with wt cells. Expression
of the full-length CD43 in the CD43-deficient cells decreased the
proliferative response, whereas the cytoplasmic deletion had no effect
despite similar expression levels. In independent experiments, similar
results were obtained with different doses of anti-CD3 (data not
shown and Table I). Therefore, the cytoplasmic domain of
CD43 is required for inhibition of T cell proliferation in primary T
cells.
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Coligation of CD43 with TCR engagement has been demonstrated to
augment the proliferative response of primary T cells (2, 6, 7, 8, 11).
The mechanism for CD43-mediated costimulation is unclear, but may
involve direct signal transduction mechanisms. To examine this, we
expressed either full-length CD43 or CD43 in which the cytoplasmic tail
had been deleted in primary T cells from CD43-deficient mice. The cells
were then stimulated with anti-CD3 alone (0.1 µg/ml) or in
combination with anti-CD43 (1.0 µg/ml) or anti-CD28 (1
µg/ml). CD43-deficient T cells that had been infected with a control
retrovirus did not respond to CD43 coligation. In contrast,
retrovirally infected wt T cells and CD43-deficient T cells expressing
either the full-length CD43 or the cytoplasmic deletion had an
augmented proliferative response when stimulated with a combination of
anti-CD3 and anti-CD43 Abs (Fig. 6). All
cultures responded to costimulation with anti-CD28 (Table I). Thus,
in contrast to the antiadhesive and antiproliferative effects of CD43,
the cytoplasmic tail of CD43 is not required for the generation of a
costimulatory signal by Ab.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Certain structural features of CD43 have been thought to be critical to the ability of CD43 to modulate T cell adhesion and activation. In particular, the large size and abundant glycosylation of the extracellular domain have been proposed to form a barrier to effective intercellular contact and receptor ligand engagement. In support of this, transfection of HeLa cells with CD43 has been shown to decrease their adhesive properties, which is reversed upon treatment with neuraminidase (27). In addition, study of CD43-deficient mice has demonstrated that the T cells are hyperproliferative as well as having increased adhesive properties (1, 2). CD43 also influences lymphocyte migration (28, 29). Although these data are consistent with such a model, they do not exclude a role for the cytoplasmic tail in CD43 function.
CD43 has a large cytoplasmic tail (124 amino acids in the mouse) that has been conserved through evolution, suggesting an important function for this part of the protein (30). Data from several groups have suggested that CD43 can transduce a signal. Ligation of CD43 resulted in the activation of signaling pathways in human monocytes and a human T cell line (31, 32, 33). Treatment of cells with PMA has been shown to result in hyperphosphorylation of the cytoplasmic tail of CD43 (34, 35). Recent studies have demonstrated that ligation of CD43 on human T cells with the mAb L10 led to the phosphorylation of the adapter protein Shc, as well as the formation of a Shc/Grb2 complex. In addition, phosphorylation of Vav was detected following CD43 ligation as well as activation of components of the mitogen-activated protein kinase pathway (17). CD43 also interacts with elements of the actin cytoskeleton through the linker proteins Ezrin and Moesin. These interactions mediate the distribution of CD43 on the cell and its localization to the cellular uropod (18, 19).
Given the conflicting models of CD43 function, we chose to examine the structural requirements for the regulation of cell adhesion and activation in a T cell line and primary murine T cells. Expression of the extracellular domain of CD43 failed to inhibit homotypic aggregation in a human T cell line, whereas expression of a chimeric protein containing the cytoplasmic domain of CD43 did inhibit cell-cell contact. These data suggest that the cytoplasmic tail of CD43 is both necessary and sufficient to mediate the antiadhesive effects of this protein. This suggests that the CD43 regulates cell adhesion by a mechanism other than steric hindrance.
To confirm and extend the observations made in the cell line, we examined the role of the cytoplasmic tail of CD43 in regulating T cell proliferation. We and others have demonstrated that T cells from CD43-deficient mice have an increased proliferative response to TCR engagement as compared with wt T cells (1, 2). By the use of a retroviral infection system, we expressed full-length or mutant CD43 proteins in T cells from CD43-deficient mice. Expression of the full-length protein resulted in a decrease of the proliferative response, whereas the mutant protein lacking the cytoplasmic domain failed to effect proliferation. Surface expression of the transduced proteins was equivalent for each construct, but was not quite as high as wt levels, perhaps accounting for the failure of the full-length CD43 to decrease T cell proliferation completely to wt levels. The failure of the cytoplasmic deletion mutant to restore wt function to the CD43-/- cells may indicate that CD43 influences cell signaling. Alternatively, the inability of this protein to interact with the cytoskeleton may alter the distribution of CD43 in a way that precludes its function. In addition, recognition of the retrovirally expressed proteins by the glycoform-specific CD43 mAb clone S7 (36) suggests that these proteins are correctly glycosylated; however, it is possible that there are some undetected defects in glycosylation in the mutant proteins that render them nonfunctional.
In contrast to the above findings, we find that costimulation mediated by anti-CD43 mAb does not depend upon the cytoplasmic tail. This suggests that direct signaling through CD43 is not required for this effect. This is in contrast to an earlier study in which the cytoplasmic domain of CD43 was found to be essential for costimulation (6). Park et al. demonstrated that engagement of CD43 by a cell-bound ligand on the surface of Daudi cells interacting with transfected human CD43 on a murine hybridoma required the cytoplasmic domain of CD43 to induce IL-2 production. We have examined Ab-mediated costimulation through CD43 on the surface of primary murine T cells. Costimulation through CD43 in this circumstance requires plate immobilization of anti-CD3 and anti-CD43 mAb. Thus, it is possible that the Ab-mediated costimulation we have measured is fundamentally different from that induced by cell-bound ligand. Cross-linking by plate-immobilized anti-CD43 may lead to a redistribution of CD43 on the cell surface, or in fact result in a loss of CD43 expression, rendering the area of the TCR relatively CD43 deficient and augmenting TCR signal transduction events (37). Alternatively, this high degree of cross-linking may in some way bypass the requirement for cytoskeletal linkage, allowing for costimulation in the absence of the cytoplasmic domain.
This study suggests that the regulation of cell adhesion and activation by CD43 cannot be accounted for exclusively by steric hindrance. Examination of the structural features of CD43 required for function in a human T cell line, as well as in primary murine T cells, demonstrates a critical role for the cytoplasmic domain. Further study of the intracellular pathways regulated by CD43 will undoubtedly yield important insights into the regulation of T cell function.
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Acknowledgments |
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R cDNA and Ab. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Jonathan M. Green, Washington University School of Medicine, Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address:
3 Abbreviation used in this paper: wt, wild type.
Received for publication July 15, 1998. Accepted for publication January 11, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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