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*
Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital Campus, London, United Kingdom; and
Department Biologia Cellulare e dello Sviluppo, Universitá "La Sapienza," Rome, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-IFN-treated EC monolayers. Frequencies of anti-DR17,
IL-2-secreting T cells were fourfold higher in the T cells that
transmigrated through a monolayer of DR17-expressing EC. Similar
increases were seen in TT-specific, DR7-restricted T cells that
transmigrated through TT-pulsed, DR7-expressing EC. To examine more
directly the effects of cognate recognition of Ag presented by EC, T
cell clones were used. For clones that proliferated in a
costimulation-independent manner to Ag presented by EC, cognate
recognition arrested transmigration. In contrast, Ag
presentation by EC to B7-dependent T cell clones, which do not
proliferate following cognate recognition of EC, enhanced the rate of
transendothelial migration. These data suggest that Ag presentation by
EC may serve to augment the recruitment of Ag-specific T cells into
tissues and that proliferation and transmigration are mutually
exclusive T cell responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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EC also play a key role in the immune surveillance by mediating T cell recruitment into tissue, as a result of chemokine (12, 13), selectin (14, 15), and integrin (16, 17, 18) display.
It is well known that lymphocyte recirculation and the localization of Ag-specific T cells at sites of inflammation are not random events. Naive and memory T cells exhibit distinct patterns of recirculation (19). Naive T cells migrate from blood into lymphoid tissues via high endothelial venules. Memory and activated T cells, in contrast, can recirculate between blood and the tissues. The differences between these patterns of traffic are determined by the different cell surface arrays of adhesion molecules displayed by naive and memory T cells (20). Other T cell surface molecules, named addressins, can even determine the preferential homing of T cells in a particular body compartment (21, 22, 23). As a counterpart, a number of adhesion receptors have been identified on EC that participate in the interaction of T cells with the venular EC in secondary lymphoid tissues and with activated endothelium in inflamed tissues (16, 17, 18, 24, 25, 26).
Although these and other studies have helped to shed light on the Ag-independent molecular mechanisms underlying these events, very little is known of the effect, if any, that cognate recognition of endothelial cells has on T cell recruitment. Most studies have emphasized the importance of Ag-independent expression of certain surface molecules by T cells for their migratory ability (20) and localization preferences (21, 22, 23). However, indirect evidence exists that suggests that TCR engagement may, at least, facilitate T lymphocyte recruitment. For example, it is clear that the integrin interaction requires activation of LFA-1 and VLA-4 on the T cell, to induce the high affinity conformation of the integrin (27, 28, 29, 30). However, the mechanism of integrin activation is not yet clear. One possibility is that chemokines present at the EC surface may contribute to this activation step. An alternative mean of inducing the high affinity integrin conformation is signaling through the TCR/CD3 complex (27, 28). The problem posed by this finding is that the high affinity integrin conformation persists only for a short time, such that it would be lost by the time a T cell that was activated in a lymph node had recirculated to the site of inflammation.
Finally, the role of Ag in specific recruitment of T cells has also been emphasized by recent data that suggested that the presence of Ag in a tissue can attract and retain Ag-specific T cell clones in vivo (31), although the molecular basis of this phenomenon were not investigated.
The purpose of this study was to reinvestigate the immunological role of Ag-specific interactions between MHC class II-expressing EC and CD4+ T cells. In particular, given the apparent "neutral" effect that Ag recognition of EC had on resting memory T cells in our hands, the possibility that such encounter might instead influence transendothelial migration of Ag-specific activated and resting memory T cells, thereby contributing to their recruitment, was analyzed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The synthetic influenza virus hemagglutinin (HA) peptides (HA 307–319 and HA 100–115) were synthesized by the Imperial Cancer Research Fund (ICRF) Peptide Unit and kindly provided by Dr. Hans Stauss. Tetanus toxoid (TT) was purchased from Evans Medical (Leatherhead, U.K.). Purified protein derivate (PPD) was a kind gift of S. Wilson (The London Hospital, London, U.K.).
Monoclonal Abs
The following mAbs were used in purified form for preparation of CD4+ T cells: Leu-19 (anti-CD56; Becton Dickinson, Cowley, U.K.), mouse anti-human Ig (Fab-specific; Sigma, Poole, Dorset, U.K.), L243 (anti HLA DRa; American Type Culture Collection (ATCC), Manassas, VA), and OKT8 (anti-human CD8; ATCC). The OKT8 and L243 mAbs were purified from culture supernatant on protein A-Sepharose beads by standard methods. Eluted Ab was dialyzed against three changes of PBS. The mAb anti-CD45RA (SN 130, gift of G. Janossy, Royal Free Hospital, London) (32), was purified as described above. The mAb 24 (anti-LFA-1; 33 was a kind gift of N. Hogg (ICRF, London). The Anti-VCAM mAb was kindly donated by D. Haskard (Imperial College School of Medicine, London), and the anti-VLA-4 was purchased from Serotec (Kidlington, U.K.).
Separation and culture of HUVEC
Endothelial cells (HUVEC) were isolated from human umbilical
cord veins by collagenase (Sigma) treatment according to a modification
of the technique described by Jaffe et al. (34) and depleted of
contaminating MHC II+ cells using the Dynabead technique
(Dynal Ltd., Merseyside, U.K.) according to the manufacturer’s
instructions. Recovered cells were serially subcultured at 37°C with
5% CO2 in Medium 199 (Sigma) supplemented with 20% heat
inactivated FCS, 2 mM glutamine (Flow Labs., Irvine, U.K.), 150 mg/ml
Endothelial Cell Growth Supplement (Sigma), 12 U/ml heparin (Sigma),
100 IU/ml penicillin (Flow), 100 µg/ml streptomycin (Flow), and 2.5
µg/ml Fungizone (ICN Biomedicals, Costa Mesa, CA) in gelatin
(Sigma)-coated tissue culture flasks (Greiner Labortechnik, Dursley,
U.K.). At confluence, HUVEC were detached from the culture flasks,
using a solution of 0.125% trypsin in 0.2% EDTA (Life Technologies,
Paisley, U.K.), and passaged. For functional assays, HUVEC were used in
the assays at passage 4–10. Before use in assays, HUVEC were cultured
in the presence of 500 U/ml of -IFN (kindly provided by T. Meager,
National Institute for Biological Standards and Controls, U.K.) to
induce expression of MHC class II molecules. Confirmation of the
endothelial lineage of the cells obtained was achieved by staining with
anti-von Willebrand factor (DAKO) and anti-CD31 (DAKO,
Ely, U.K.) mAbs.
Cell lines
EBV-transformed B-lymphoblastoid cell lines (B-LCL), from the 10th International Histocompatibility Workshop, were cultured in RPMI 1640 tissue culture medium (Flow) supplemented with 10% FCS, 2 mM glutamine, 50 IU/ml penicillin, and 50 µg/ml streptomycin.
The IL-2-dependent murine T cell line CTLL-2 (European Collection of Animal Cell Cultures, Salisbury, U.K.) was cultured in RPMI 1640 medium, supplemented with 2 mM L-glutamine, 50 IU/ml penicillin, 50 µg/ml streptomycin, 10 U/ml of human rIL-2 (Boehringer Mannheim, Mannheim, Germany), and 10% FCS. The cells were cultured in 25-cm2 flasks and were subcultured every 3 days. Before use in a proliferation assay, the CTLL-2 cells were washed twice and cultured overnight in normal culture medium, but without added rIL-2.
Purification of CD4+ CD45RO+ T cells
PBMC were obtained by Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) centrifugation of heparinized blood, washed twice, and resuspended in RPMI 1640 medium supplemented with 10% FCS, 2 mM glutamine, 50 IU/ml penicillin, and 50 µg/ml streptomycin. The cell preparation was then depleted of adherent cells by two 45-min rounds of adherence to plastic on tissue culture dishes at 37°C. The nonadherent cells were subsequently collected and incubated with a mixture of purified mAbs (L243, OKT8, Leu-19, mouse anti-human Ig, and SN130) at saturating concentrations for 30 min at 4°C. The cells were then washed twice to remove excess Ab and further enriched by magnetic immunodepletion. Briefly, mAb-treated cells were incubated with magnetic microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany) coated with sheep anti-mouse Ig for 15 min at 4°C, and bead/mAb-coated cells were removed by passage through a magnetic column (miniMAC system; Miltenyi). The purified cells were resuspended in medium ready for the proliferation assay, and accessory cell contamination was assessed by culture with 1 µg/ml PHA in a 48-h assay.
T cell clones
Clones HC3, HC6, and NF4, specific for HA 307–319 and restricted by DRB1*0101, were generated as described previously (35, 36). Clones LR34 and LR47, specific for HA 307–319 and restricted by DRB1*0401, were derived from PBMC isolated from a DR 4,15 individual by stimulating PBMC with purified influenza hemagglutinin (HA 5 µg/ml). The clones were maintained in culture by weekly stimulation with autologous PBMC, HA peptide, and rIL-2 (Boehringer Mannheim) in RPMI 1640 medium supplemented with 10% human serum, 2 mM glutamine, 50 IU/ml penicillin, and 50 µg/ml streptomycin. For use in experiments, the T cells were purified by isolation on a Ficoll-Paque gradient 7 days after restimulation and washed five times by low speed centrifugation (210 g, 5 min) before use, to exclude any contamination by accessory cells.
T cell proliferation assays
T cell clones (104 cells/well) were cultured in the presence of B-LCL (2 x 104/well), treated with 120 Gy x-irradiation, or EC (2 x 104/well), treated with 30 Gy x-irradiation, in flat-bottom microtiter plates, in a total volume of 200 µl. The stimulator cells were prepulsed overnight with peptide and then washed to remove any soluble peptide. Wells were pulsed with 1 µCi of [3H]TdR (Amersham International, Amersham, U.K.) after 48 h, and the cultures were harvested onto glass fiber filters (Wallac, Turku, Finland) 18 h later. Proliferation was measured as [3H]TdR incorporation by liquid scintillation spectroscopy.
Lymphocyte transmigration assays
The transmigration experiments were conducted using HUVEC monolayers grown on Costar Transwell tissue culture well inserts (diameter 24.5 mm), which contained polycarbonate membranes with a 3-µm pore size (Costar, High Wycombe, U.K.). EC (105) were seeded onto fibronectin-coated (50 µg/ml; Sigma) polycarbonate membranes overnight to form a monolayer. In some experiments, Ag was added for 16–18 h before the transmigration assay. Purified resting CD4+ CD45RO+ T cells (4 x 106) in RPMI 1640 supplemented with 10% HS were added into each insert and left to migrate through the monolayer; the well volume was also replaced with fresh media. T cells were left to migrate overnight; then each insert was removed in turn and the base was thoroughly washed with media from the well to detach any transmigrated cell still loosely attached. On average, 10–20% of the seeded T cells were recovered from the lower chamber. The transmigrated cells were then counted and used for the limiting dilution analysis assay. In other experiments using T cell clones, T cells (2 x 106) were placed into each insert and left to migrate through the EC monolayer. After 1 h, the number of migrated T cells was determined by counting the lymphocytes present in the well media. This was done at different time points for the next 48 h. In these experiments, results are expressed as percentage of transmigrated cells.
Limiting dilution analysis assays
Responder T cells were diluted into seven serial twofold
dilutions, and twenty-four replicate wells of each dilution were plated
out, in 50 ml, in U-bottomed 96-well plates (Costar), with responder
cell number decreasing from 2 x 104 to 0.03125
x 104 per well. The stimulator cells (either B-LCL or
PBMC) were -irradiated (192 Gy for the B-LCL or 50 Gy for the PBMC),
and 1 x 105 PBMC or 5 x 104 B-LCL
were added to each well. After 72 h incubation the culture plates
were -irradiated (25 Gy) to prevent further proliferation of
responder cells, and 1 x 103 indicator CTLL-2 cells
were added to each well. After 8 h, the plates were labeled with
[3H]TdR (1 µCi/well), and proliferation of the CTLL-2
was assessed by [3H]TdR incorporation after a further
18 h incubation. Background control wells contained stimulator
cells and CTLL-2 cells, but no responder cells. Assay wells were
considered positive if proliferation exceeded the average, plus three
SD, of control wells. In all experiments, CTLL-2 proliferation to a
range of rIL-2 concentrations was measured to ensure that the CTLL-2
cells gave a dose-dependent response to IL-2.
Statistical analysis
Frequencies of alloreactive or Ag-specific CD4+ T cells were calculated using a maximum likelihood statistical program, based on the method of Finney (37). The proportion of negative wells at each sample size of responder cells is linearly related to the frequency of responder cells, according to the Poisson distribution, -logePneg = fX, where Pneg is the proportion of negative wells, f is the frequency of responder cells, and X is the sample size of responder cells/well.
In addition, 95% confidence limits of the frequencies and
2 estimates of probability were calculated. Frequencies
are regarded as different if their 95% confidence limits
(approximately two SD) do not overlap.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Given that the central role of EC during an immune response is to facilitate selective access of leukocytes to inflamed tissues, one attractive possibility is that TCR engagement by EC-presented Ags augments the recruitment of Ag-specific T cells into the tissue. Consistent with this hypothesis, it has been recently shown that TCR engagement delivers a "stop" signal to ICAM-1-triggered T cell locomotion on planar phospholipid bilayers (38).
The effect of cognate recognition on transmigration of CD4+ T cells was investigated by analyzing the frequencies of allospecific and Ag-specific purified CD45RO+ T cells before and after overnight migration through a monolayer of EC expressing the relevant ligand. CD45RO+ T cells were selected for these experiments in relation to our previous finding that they are neither activated nor rendered unresponsive by cognate recognition of EC (9). An attempt to use CD45RA+ T cells as a control was unsuccessful, in that less than 1% of the total input of T cells migrated.
Following overnight incubation on allogeneic EC monolayers, the
frequencies of specific T cells were found to be two- to fourfold
increased following transendothelial migration. The results are
summarized in Tables I and
II. The highly purified
CD45RO+ T cells used in the transmigration assays were not
activated by Ag-pulsed EC, as is illustrated by a proliferation assay
performed in parallel and reported below each panel. As shown in Table I
, expt. 1, the frequency of DR17-specific alloreactive T cells
was twofold higher in the cells that had migrated through a
DR17-expressing EC monolayer, compared with the frequency in the
starting population. No change in the frequency of T cells specific for
a third party alloantigen (DR1) was seen. Nontreated EC did not caused
preferential migration of allospecific T cells. A similar increase in
frequency of T cells specific for the recall Ag TT was seen following
transmigration through an EC monolayer expressing an autologous DR
type, and pulsed with TT (Table I, expt. 2). No change in the frequency
of T cells specific for a third party Ag-purified protein derivative
was observed. Confirmation that the increase in frequency was due to
cognate recognition was provided by the finding that addition of the
anti-DR mAb L243 (1 µg/ml, optimal dose for inhibition of
alloproliferation, JGM) partially inhibited this effect (Table I, expt. 3), having no effect on the frequency of T cells reactive to
third party DR15-positive alloantigen. In these experiments, EC
monolayers were treated with L243 mAb before seeding the T cells to
avoid nonspecific interference with Ag-independent T cell binding and
migration. It is possible that fast recycling of MHC molecules on the
EC surface might account for the partial, albeit reproducible,
inhibition obtained in these experiments as compared with that observed
in other systems.
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, expt. 4, this led to a 50% reduction in the frequency of
DR17-reactive T cells in the transmigrated population. In contrast, no
diminution in the frequency of T cells specific for third party HLA-DR7
molecules, not expressed by the EC monolayer, was seen. These
observations suggest that the mechanism by which Ag recognition
enhances T cell migration is, at least in part, the activation of
integrins following TCR ligation or coligation with other relevant
molecules. Transmigrated T cells did not proliferate, but remained
responsive to the DR molecules expressed by the EC, as it is shown by
the limiting dilution assays. Indirect evidence for this is provided by
the observation that when the T cell preparation was contaminated with
autologous APC, T cell proliferation to the EC was accompanied by a
decreased frequency against the relevant DR molecule after
transmigration (Table II).
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One possible interpretation of the above results is that migration through an EC monolayer displaying specific ligand in some way preactivates the T cell, such that subsequent Ag reactivity is enhanced. To address this point we analyzed the influence of cognate recognition on the transmigration of T cell clones.
The proliferative response of T cell clones to Ag presented by EC is
heterogeneous and is determined by the requirement of the clone for
B7-mediated costimulation (F. M. Marelli-Berg and R. I.
Lechler, unpublished observations). Proliferation by the T cell clones
chosen for the transmigration experiments in response to peptide
presented by EC and B-LCL is shown in Fig. 1. Although all the T cell clones
proliferated in response to B cell Ag presentation, HC3 and LR34 did
not divide in response to the EC.
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, cognate
recognition accelerated transmigration by the B7-dependent clones, HC3
and LR34. Given that it has been estimated that T cell migration in
vivo occurs within an hour (39), this phenomenon might be of particular
relevance during the physiological recruitment of T cells into tissues.
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Adhesion molecule expression by B7-dependent and -independent T cell clones.
Lymphocyte strong adhesion to EC monolayers and possibly
subsequent migration are likely to be effected by integrin-mediated
interactions (16, 24, 25, 26). The expression of LFA-1 and VLA-4 molecules
on the T cell clones used in the transmigration assay was analyzed by
cytofluorometric analysis. The clones were examined 7 days after Ag
stimulation, before being used in a transmigration assay. As shown in
Fig. 3, the B7-independent T cell clones
LR47 and NF4 expressed higher levels of both LFA-1 and VLA-4 as
compared with the B7-dependent T cell clones LR 34 and HC3. None of the
clones constitutively expressed the activated LFA-1 reporter epitope
recognized by the mAb 24. These results raise the possibility that the
degree of B7 dependence of a T cell clone relates to its expression of
adhesion molecules, such as LFA-1 and VLA-4, and that differences in
the levels of these molecules may have contributed to the different
characteristics of these clones in the transmigration assays.
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The above data demonstrate that cognate recognition on EC, while
not inducing full T cell activation of costimulation-dependent T cell
clones, did increase the rate of transmigration. To further explore the
role of T cell activation in transendothelial migration, we examined
the effect of inducing anergy in T cells on their capacity to
transmigrate. The T cell clone HC3 was rendered nonresponsive by
exposure to DR1-expressing thyroid epithelial cells (TFC) prepulsed
with the relevant peptide, as previously described (40). The loss of Ag
reactivity following overnight culture with TFC is illustrated in Fig. 4a). After overnight
coculture, the anergic T cells and T cells incubated in medium alone
were seeded onto -IFN-treated, DR1+ EC monolayers,
either prepulsed or not with the cognate peptide, and the number of
transmigrated T cells was then monitored. Anergic T cells retained the
ability to proliferate in response to exogenously added IL-2. As seen
in Fig. 4b, anergic T cells completely lost the ability to
migrate through the EC monolayer. This was also true in the absence of
cognate Ag (data not shown). This impairment appeared to be persistent,
as judged by the complete absence of migration even after 26 h.
The expression of VLA-4 and LFA-1 on T cells was not altered by the
induction of anergy (data not shown), while CD40 expression was
down-regulated, as previously described (41). Anergic T cells did not
bind the mAb 24 before or after seeding onto the EC monolayer (data not
shown), although this cannot rule out transient expression of the
epitope. Coculture with the EC did not result in the recovery of
responsiveness by anergic T cells while the reactivity of T cells
cultured in medium alone was unaffected, independently of the
occurrence of nonspecific or peptide-enhanced transendothelial
migration (Fig. 4c).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The observations described in this study have in vivo relevance to the recruitment of either resting memory T cells or recently activated T cells into inflamed tissues. Naive T cells, in contrast, do not recirculate into extralymphoid tissue and are selectively activated in the lymph node (19, 39). The transmigration experiments revealed that cognate recognition of Ag presented by EC influenced the extent of transmigration for all the T cell populations studied. For the CD45RO+ T cells, it appeared that migration across EC monolayers expressing the relevant Ag over a period of 16 h enhanced two- to fourfold the frequency of Ag-specific T cells in the migrated T cell population. Had it been technically possible to measure such frequencies at an earlier time, the observed enhancement might have been more pronounced. This prediction is suggested by the results obtained when the influence of cognate recognition on B7-dependent T cell clones was analyzed. In these experiments, the migration rate of T cells through EC monolayers was greatly enhanced in the first few hours following seeding onto the Ag-pulsed EC monolayers. Given that T cell migration in vivo is a rapid process, the physiological relevance of this observation might be of particular importance during T cell recruitment in vivo. Although it is clear that the majority of T cell trafficking into tissues is regulated by Ag-nonspecific mechanisms (16, 20, 39), these data suggest that Ag display by EC can facilitate this process. A recent study analyzing T cell locomotion on phospholipid layers has suggested that TCR engagement might in fact initiate this process by delivering an arrest signal to T cells (38).
In contrast with the enhanced migration that was observed with the
B7-dependent T cell populations, transmigration was markedly inhibited
for the clones that proliferated in response to EC Ag presentation.
These findings have relevance to the debate surrounding whether
-IFN-treated EC can initiate T cell proliferation. The results
obtained here suggest that proliferation and transmigration are two
alternative, and mutually exclusive, responses of T cells to Ag
recognition. Given that the function of EC is to facilitate T cell
entry into inflamed tissues, it would be undesirable for EC to induce T
cells to proliferate.
The mechanism whereby cognate recognition promoted transmigration has
yet to be fully defined. However, the finding that the frequency of
Ag-specific T cells that had transmigrated was significantly reduced by
removal of cells expressing the high affinity form of the integrin
LFA-1 suggests that activation of integrins may provide at least part
of the explanation. The need of a T cell to acquire the activated
conformation of adhesion molecules to transmigrate across EC may also
explain the data obtained with the T cells that had been rendered
anergic following Ag recognition on -IFN-treated epithelial cells.
Various defects in intracellular signaling have been defined in anergic
T cells. One such defect is in the activation of the Ras pathway (42),
which is involved in cytoskeletal rearrangement, as well as in IL-2
gene transcription. We have previously reported that anergic T cells
can regulate neighboring T cells (43, 44). The reduced mobility of
anergic T cells, as observed here, is consistent with their persistence
at a site of inflammation to regulate other cells with unwanted
specificities, such as those reactive with self Ags.
Finally, the physiological relevance of these findings to T cell recruitment during an inflammatory response depends upon the ability of EC to process and present Ags that are sequestered in the underlying tissue. There is in vitro evidence that suggests that this occurs (45). Clearly, in the context of allotransplantation, EC display donor MHC alloantigens, and this could contribute to the recruitment of allospecific T cells into the graft. Further investigation of the issues raised by these data will necessarily involve the use of in vivo models.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Robert I. Lechler, Department of Immunology, Imperial College School of Medicine, Hammersmith Hospital Campus, DuCane Road, London W12 0NN, U.K. E-mail address:
3 Abbreviations used in this paper: EC, endothelial cells; B-LCL, B-lymphoblastoid cell line; TT, tetanus toxoid; VLA, very late Ag; HA, hemagglutinin; TFC, thyroid follicular epithelial cells.
Received for publication June 18, 1998. Accepted for publication September 28, 1998.
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and inhibition by IL-4 and IL-13. J. Immunol. 154:1870.[Abstract]
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J. E. Greening, T. I.M. Tree, K. T. Kotowicz, A. G. van Halteren, B. O. Roep, N. J. Klein, and M. Peakman Processing and Presentation of the Islet Autoantigen GAD by Vascular Endothelial Cells Promotes Transmigration of Autoreactive T-Cells Diabetes, March 1, 2003; 52(3): 717 - 725. [Abstract] [Full Text] [PDF]
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L.-P. Berg, M. J. James, M. Alvarez-Iglesias, S. Glennie, R. I. Lechler, and F. M. Marelli-Berg Functional Consequences of Noncognate Interactions Between CD4+ Memory T Lymphocytes and the Endothelium J. Immunol., April 1, 2002; 168(7): 3227 - 3234. [Abstract] [Full Text] [PDF]
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 M. H. Hammer, G. Schroder, K. Risch, A. Flugel, H.-D. Volk, M. Lehmann, and T. Ritter Antigen-Dependent Transgene Expression in Kidney Transplantation: A Novel Approach Using Gene-Engineered T Lymphocytes J. Am. Soc. Nephrol., February 1, 2002; 13(2): 511 - 518. [Abstract] [Full Text] [PDF]
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M. H. Hammer, Y. Zhai, M. Katori, T. Ritter, H.-D. Volk, A. J. Coito, and J. W. Kupiec-Weglinski Homing of In Vitro-Generated Donor Antigen-Reactive CD4+ T Lymphocytes to Renal Allografts Is {{alpha}}4{beta}1 But Not {{alpha}}L{beta}2 Integrin Dependent J. Immunol., January 1, 2001; 166(1): 596 - 601. [Abstract] [Full Text] [PDF]
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F. M. Marelli-Berg, D. Scott, I. Bartok, E. Peek, J. Dyson, and R. I. Lechler Activated Murine Endothelial Cells Have Reduced Immunogenicity for CD8+ T Cells: A Mechanism of Immunoregulation? J. Immunol., October 15, 2000; 165(8): 4182 - 4189. [Abstract] [Full Text] [PDF]
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 R. A. Hawkins, R. G. Rank, and K. A. Kelly Expression of Mucosal Homing Receptor alpha 4beta 7 Is Associated with Enhanced Migration to the Chlamydia-Infected Murine Genital Mucosa In Vivo Infect. Immun., October 1, 2000; 68(10): 5587 - 5594. [Abstract] [Full Text] [PDF]
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