By
From the * Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford
University, Stanford, California 94305; Center for Molecular Biology and Medicine, Veterans Affairs
Health Care System, Palo Alto, California 94304; and § Department of Microbiology and
Immunology, The Cancer Center of the University of Rochester School of Medicine and Dentistry,
Rochester, New York 14642
The homing of lymphocytes from the blood is controlled by specialized processes of lymphocyte-endothelial cell interaction. Interference with these processes offers the potential to manipulate lymphocyte traffic, and thus to modulate normal and pathologic immune and inflammatory responses. We selected antilymphocyte monoclonal antibodies (mAbs) for inhibition of
lymphocyte binding in vitro to lymph node high endothelial venules (HEV), specialized vessels
that support lymphocyte recruitment into lymph nodes. mAb L11 blocks T cell binding to
lymph node and Peyer's patch HEV and inhibits T cell extravasation from the blood into organized secondary lymphoid tissues. In contrast, L11 has no effect on lymphocyte binding to purified vascular ligands for L-selectin, 4
7, or LFA-1, suggesting that it inhibits by a novel
mechanism. The L11 antigen is CD43, a sialomucin implicated in vitro in regulation of lymphocyte activation, whose expression is often dysregulated in the Wiskott-Aldrich syndrome.
CD43 represents a novel target for experimental and therapeutic manipulation of lymphocyte
traffic and may help regulate T cell distribution in vivo.
Regulated trafficking of lymphocytes through secondary lymphoid tissues is key to systemic immunity and is
controlled by active mechanisms of lymphocyte-endothelial
cell (EC) recognition (1, 2). Recruitment of lymphocytes
from the blood has been separated into multiple sequential
steps characterized as contact initiation ("tethering"), rolling,
pertussis toxin-sensitive G A number of adhesion molecules involved in lymphocyte homing via high endothelial venules (HEV) have been
identified. In Peyer's patches (PP), the adhesion cascade for
naive lymphocytes appears to involve a series of overlapping adhesion events with L-selectin, and to a lesser extent
Lymphocyte-HEV recognition is readily studied in vitro
in analyses of lymphocyte binding to HEV in frozen tissue
sections in an assay developed by Stamper and Woodruff
(8). In this assay, the molecular elements involved both in
primary adhesion and activation-dependent interactions
have been identified or shown to participate; thus, it represents a powerful tool for dissecting this cellular event in its
molecular basis (9; see Discussion). Therefore, to identify
novel molecular targets for controlling lymphocyte homing, we selected mAbs for their ability to block lymphocyte
binding to HEV in frozen sections. We describe here an
mAb, L11, that inhibits lymphocyte-HEV interaction in vitro
and lymphocyte recruitment to LN, PP, and spleen in vivo. Inhibition is selective for T cells, suggesting an experimental and therapeutic approach and potentially a physiologic
mechanism for differential control of T versus B cell homing. We demonstrate that the L11 antigen is CD43, a major
membrane sialoglycoprotein of hematopoietic cells (10,
11), implicated in the regulation of T cell activation and
adhesion in vitro.
Antibodies.
mAb L11 was produced by immunizing Fisher
344 rats four times at 3-wk intervals with the monocytoid cell
line WEHI78/24 (12; gift of R. Coffman, DNAX, Palo Alto, CA).
Spleen cells were fused with SP2/0 myeloma cells (American
Type Culture Collection; Rockville, MD) using traditional polyethylene glycol fusion methods. Hybridoma supernatants were
screened for their ability to block binding of peripheral lymph
node (PLN) and mesenteric lymph node (MLN) lymphocytes to
PLN HEV in Stamper-Woodruff frozen section assays (described
below). L11 hybridoma was cloned three times by limiting dilution. The isotype (IgG2a) was determined by Ouchterloney analysis (ICN Biomedicals, Inc., Costa Mesa, CA). FITC-labeled
Thy1.2, anti-CD43 mAb S7, and FITC-labeled S7 were purchased from PharMingen (San Diego, CA) and PE-conjugated
goat anti-rat IgG was purchased from Jackson ImmunoResearch
Labs. (West Grove, PA). RA3-6B2 (anti-B220; gift of R. Coffman;
13) was produced, purified, and FITC-conjugated. MECA367
(anti-mouse mucosal addressin [MAdCAM-1]; 14), MJ64, anti- mouse CD44 (15), and rat IgG negative control mAbs 9B5 (16) and 30G12 (anti-T200) were prepared in the laboratory.
Stamper-Woodruff Frozen Section Assays.
Modified Stamper-Woodruff frozen section assays were performed (8, 17) using isolated
BALB/c PLN and MLN lymphocytes (2 × 107/ml) mixed 1:1
with tretramethylrhodamine B isothiocyanate (TRITC)-labeled rat
MLN lymphocytes in DMEM (BioWhittaker, Walkersville, MD)
without bicarbonate containing 20 mM Hepes, pH 7.0, and 0.1%
(vol/vol) fetal bovine serum (assay buffer). TRITC labeling of rat
internal standard cells (not recognized by L11) was performed
as previously described using 1.5 µg TRITC/ml of assay buffer
for 20 min at 37°C (18). Cells were preincubated with isotypematched control mAb (30G12) or with L11 (0.25 µg/106 cells) for
20 min on ice and added to freshly cut PLN frozen sections (100 ml/section) and allowed to bind for 30 min with constant rotation
(76 rpm) at 4°C. Slides were gently placed in 1.5% gluteraldehyde
in PBS containing 2 mM Ca2+ and 2 mM Mg2+. The number of
mouse and rat lymphocytes bound to >30 HEV on each of the
quadruplicate sections was determined by fluorescence microscopy. The ratio of the number of L11-treated cells bound/rat internal standard to the number of control antibody-treated cells bound/rat internal standard was calculated and multiplied by 100 to express sample cell binding as percent of control cell binding. T cells were isolated by negative selection on anti-B cell and antimacrophage columns (R & D Sys., Inc., Minneapolis, MN) and were >97% Thy1+. B cells were identified in mixed populations
by prestaining cell suspensions with FITC-conjugated anti-B220.
Data represents the mean and standard error of four experiments.
Adhesion Assays.
The ability of L11 to inhibit lymphocyte
binding to purified vascular ligands was assessed as previously described (19, 20).
Flow Cytometry.
BALB/c MLN and PLN lymphocytes were
immunostained with L11 (1 µg/106 cells) or isotype-matched control mAb, PE-conjugated mouse anti-rat IgG followed by FITCconjugated anti-Thy-1. Cells were analyzed on a FACScan® (Becton Dickinson, San Jose, CA). Cross-blocking experiments were
performed by preincubating lymphocytes with 9B5, MJ64, S7, or
L11 (5 µg/106 cells) for 20 min and then adding FITC-labeled
S7, MJ64, or 30G12. After an additional 20 min, incubation cells
were washed and analyzed as above.
In Vivo Homing.
Lymphocytes from BALB/c MLN, PLN,
and spleens were labeled with 10 mM Cell-Tracker Orange (Molecular Probes Inc., Eugene, OR) according to the manufacturer's instructions or with TRITC, washed, and treated with
L11 or isotype-matched negative control mAb (1 µg/106 cells)
for 20 min. Cell suspensions were diluted and centrifuged. The
supernatant was then removed and 5 × 107 cells were resuspended in 0.5 ml of HBSS (BioWhittaker) and injected via the
tail vein. In other experiments, excess antibody (50 µg) was coinjected with cells. At the appropriate time point, peripheral blood was collected by heart puncture and lymphocyte suspensions prepared from lymphoid organs. Cells were stained with
FITC-conjugated anti-Thy-1 and analyzed by two-color flow
cytometry.
Transfection and Immunofluorescence.
Chinese hamster ovary P
(CHO-P) cells were transfected with mouse CD43 or mouse
MAdCAM-1 cDNA as described (21) and stained with L11 mAb
or control mAb MECA367 (anti-MAdCAM-1) followed by PEconjugated goat anti-rat IgG and visualized by fluorescence microscopy.
To identify antibodies capable of inhibiting lymphocyte trafficking, mAbs were generated and screened for
their ability to block lymphocyte binding to HEV in LN
frozen sections, using a modified Stamper-Woodruff assay
(8, 17). One antibody isolated in this screen, L11 (isotype
IgG2a), blocks T cell binding to normal and inflamed PLN
HEV by >80% (Fig. 1). Interestingly, it has much less effect on LN B cell binding. Two-color flow cytometric analysis of LN lymphocytes reveals that L11 antigen is
highly expressed by T cells but also weakly by B lymphocytes (Fig. 2), correlating with the predominant inhibitory
effect of L11 on T cells.
Inhibition of binding to HEV suggests involvement of the
L11 antigen in T cell homing. We therefore assessed the effect of L11 on short-term localization of intravenously injected lymphocytes in vivo. Pretreatment of syngeneic LN
cells with L11 results in significant inhibition of 1-h homing of T cells, but not B cells, to PLN, MLN, PP, and
spleen (Fig. 3 A). Although similar inhibition of T cell trafficking is observed whether L11-pretreated lymphocytes are washed before injection or are co-injected with excess
mAb, if lymphocytes are injected with excess antibody, significant reduction (
To further assess the fate of antibody-treated cells and
the possibility of cell damage or toxicity caused by L11,
longer-term redistribution studies were performed. Lymphocytes were labeled with 10 µM Cell-Tracker Orange,
preincubated with saturating levels of L11 or control antibody, washed, and injected into syngeneic recipients. Animals were killed at 1, 24, and 48 h. As above, 1-h homing
was blocked by L11, but by 48 h, the distribution and number of L11-treated cells in lymphoid tissues was similar
to that of control cells (Fig. 3 B).
In situ lymphocyte interactions with
HEV involve sequential overlapping engagement of L-selectin,
Immunofluorescence flow cytometry reveals that L11 antigen is highly expressed by bone
marrow neutrophils as well as T cells (not shown). This expression pattern is similar to that of CD43 (10). In addition,
the relative molecular mass of the L11 antigen, 100 kD in
Western blots (not shown), is also similar to that reported for mouse CD43 (11). Therefore, we next assessed reactivity of L11 with CHO-P cell transfectants expressing mouse
CD43 (11). L11 (Fig. 5, left) but not control mAb (Fig. 5,
right), stained CD43-transfected CHO-P cells, as did antiCD43 mAb S7 (not shown). L11 failed to stain mocktransfected CHO-P cells or CHO-P cells expressing the irrelevant antigen MAdCAM-1. Thus, L11 can recognize CD43.
To determine if the T cell antigen recognized by L11 is
CD43, LN lymphocytes were stained (at subsaturating concentrations) with L11 or S7 (detected with PE-conjugated
anti-mouse IgG) and FITC-labeled S7 or FITC-labeled
Thy-1. As shown above, double staining with FITC-Thy-1
and L11 (Fig. 2 B) yielded double-positive cells, indicating
that these molecules are both expressed by T cells. In contrast, double staining with L11 and FITC-S7 yielded a linear relationship (not shown) indicating that the molecule recognized by these mAbs are expressed equivalently on individual T cells, a pattern suggesting that the mAbs recognize a common antigen. Finally, the epitopes recognized by
L11 and S7 appear to be close or overlapping as L11 (and
S7) blocks binding of FITC-labeled S7 (Fig. 6) but not
binding of FITC-MJ64 (anti-CD44), whereas MJ64 blocks
binding of FITC-MJ64 but not FITC-labeled S7. Together these data indicate that the antigen defined by L11 on T
cells is CD43.
We have shown that anti-CD43 mAb L11 is a potent inhibitor of lymphocyte homing from the blood into lymphoid organs, including the LN, PP, and spleen. Consistent
with the preferential expression of CD43 on T cells, the effect is selective for T cell homing, although when the mAb
is co-injected in excess some redistribution in B cell trafficking can also be observed. Inhibition is not due to toxicity since there is a concurrent increase in blood levels of T
cells when homing is blocked and the distribution of L11treated cells returns to normal after 48 h.
The selective effect on T cells is unusual since most previously identified lymphocyte receptors involved in homing are shared by subsets of B cells as well, reflecting the
common mechanisms of B and T cell traffic at least to organized lymph tissues. Moreover, molecules previously implicated in homing generally influence traffic in a tissue-
selective fashion (2), whereas the effect of anti-CD43 shown
here influences trafficking to LN, PP, and even spleen to a
significant extent. This suggests an effect on an event common to T cell trafficking to diverse sites.
CD43 is an abundant leukocyte surface sialomucin that
has been implicated both in antiadhesive roles, acting as a
passive barrier to engagement of surface adhesion receptors,
and in proadhesive activities, mediated, for example, through
intracellular signaling and activation of leukocyte integrins
(e.g., LFA-1) (23). In this context, the failure of L11 to
inhibit lymphocyte rolling on PNAd or lymphocyte binding to MAdCAM-1 or ICAM-1 in vitro renders it unlikely
that it is inducing a passive barrier activity of CD43. On
the other hand, L11 might inhibit a normal proadhesive signaling activity in the context of lymphocyte homing.
However, our results are also consistent with involvement
of a previously unidentified vascular ligand for CD43, with
CD43-endothelial interaction representing an additional
step in the multistep processes of lymphocyte-HEV (and
spleen marginal sinus lining cell) interactions in vivo. In
this context it is relevant that VAP-1 has recently been implicated in lymphocyte-HEV interactions in the PLN and its
role in the multistep process of HEV interaction appears to precede that of LFA-1.
In conclusion, anti-CD43 mAb L11 inhibits lymphocyte
recruitment to lymphoid organs, acting at the level of lymphocyte-EC recognition. Inhibition is selective for T cells,
suggesting an experimental and therapeutic approach, and
potentially a physiologic mechanism, for differential control of T versus B cell homing.
i-mediated activation, and activation-dependent integrin triggering and arrest (1). Each
step may be mediated by different adhesion or activation receptors allowing specificity through use of unique combinations of receptors to create specific homing pathways
(1).
4
7, initiating interaction, L-selectin and
4
7, both participating in rolling, and G
i-linked activation-triggered arrest
that requires both
4
7 and LFA-1 (5). L-selectin, but not
4 integrins, are also implicated in lymphocyte homing to LN; in this site, L-selectin appears critical in targeting the entry of most lymphocytes and LFA-1 participates in activation-dependent arrest as well (6, 7). However, additional
molecules may be involved even in these relatively wellstudied models. For example, recent studies (Salmi, M., E.L.
Berg, E.C. Butcher, and S. Jalkanen, personal communication) raise the possibility that vascular adhesion protein 1 (VAP1) may play an important role in primary (activationindependent) lymphocyte interactions with HEV in human
LN, perhaps acting in sequence with or, for some lymphocyte subsets, as a substitute for L-selectin-initiated interactions. Moreover, the molecules involved in activation
events during lymphocyte-HEV recognition have not been
identified. In addition to its importance for understanding the physiology of lymphocyte trafficking, identification of
molecules involved in or capable of modulating lymphocyte-EC recognition may reveal novel targets for the therapeutic regulation of pathological inflammatory and immune responses.
mAb L11 Inhibits T Cell Binding to HEV In Vitro and In
Vivo.
Fig. 1.
mAb L11 inhibits T
cell binding to HEV in vitro. (A)
L11 blocks binding of total LN
lymphocytes to PLN HEV in
modified Stamper-Woodruff frozen section assays performed using isolated BALB/c PLN and MLN lymphocytes mixed 1:1
with TRITC-labeled rat MLN
cells (internal standard cells not
recognized by L11). Cells were
preincubated with isotype-matched control mAb or with L11, added to
freshly cut PLN frozen sections, and incubated for 30 min with constant rotation (76 rpm) at 4°C. The number of mouse and rat lymphocytes bound to >30 HEV on each of quadruplicate sections was determined by
fluorescence microscopy. The ratio of the number of L11-treated cells
bound/rat internal standard to the number of control antibody treated
cells bound/rat internal standard was calculated and sample cell binding
expressed as percent of control cell binding. (B) Blocking of T versus B
cells was assessed as described for total lymphocytes using T cells isolated
by negative selection (>97% Thy 1+). B cells were identified in mixed
populations by prestaining cell suspensions with FITC-conjugated antiB220.
[View Larger Version of this Image (0K GIF file)]
Fig. 2.
Two-color flow cytometric analyses of expression of L11 antigen by LN T cells (Thy 1+) and weak expression by Thy 1 cells (predominantly B cells). MLN and PLN lymphocytes were immunostained with isotype-matched control mAb (A) or L11 (B), PE-mouse anti-rat IgG and finally FITC-conjugated anti-Thy-1. Cells were analyzed using a
FACScan® and CellQuest\xa9 software; x- and y-axis are log10 fluorescence.
[View Larger Version of this Image (0K GIF file)]
30% inhibition) of B lymphocyte
homing is also observed (data not shown). Importantly,
L11-treated cells were significantly enriched in the blood of
recipients, consistent with mAb inhibition of EC interaction and recruitment rather than nonspecific or toxicity-induced clearance of injected cells from the circulation. Fluorescence microscopic examination of frozen sections of LN
following in vivo homing reveals decreased accumulation
of L11-treated cells in HEV compared to control cells, in
spite of enhanced blood levels, suggesting that the antibody
inhibits events involved in lymphocyte-HEV recognition
in vivo.
Fig. 3.
mAb L11 inhibits T cell binding to HEV in vivo. (A) L11
pretreatment inhibits T (closed bars) but not B (open bars) cell localization to PLN, MLN, PP, and spleen 1 h after intravenous injection. TRITClabeled lymphocytes were treated with L11 or isotype-matched negative control mAb for 20 min, washed, and 5 × 107 cells injected via the tail
vein. After 1 h, peripheral blood was collected by heart puncture and
lymphocyte suspensions prepared from lymphoid organs were stained with
FITC-conjugated anti-Thy-1, spiked with internal standard fluorescent
beads for enumeration, and analyzed by two-color flow cytometry. (B)
Homing of L11-pretreated T cells returns to that of control cells over 48 h. Redistribution studies were performed as described for A using cells labeled with 10 mM Cell-Tracker Orange.
[View Larger Version of this Image (0K GIF file)]
4
7, and LFA-1 (5). To determine if L11 was directly
inhibiting engagement of these adhesion receptors, the
ability of L11 to inhibit lymphocyte binding to purified
vascular ligands was assessed. L11 had no effect on T cell rolling on the L-selectin ligand peripheral node addressin (PNAd; data not shown) or on binding to the
4
7 ligand
MAdCAM-1 (Fig. 4 A). As described (22), lymphocytes require activation to bind the LFA-1 ligand intracellular adhesion molecule 1 (ICAM-1); L11 had no effect on this interaction when integrins were triggered by replacement of
Mg2+ with Mn2+ in the binding buffer (Fig. 4 B). These results suggest that the L11 antigen is not acting as a receptor
for known vascular adhesion ligands, and that L11 does not
directly inhibit engagement of these receptors.
Fig. 4.
L11 fails to block
binding of lymphocytes to MAdCAM-1 or ICAM-1. (A) anti7 mAb cocktail containing
FIB504, FIB30, and DATK32 (26) blocks binding of MLN
lymphocytes to purified MAdCAM-1 and (B) anti-LFA-1
mAb blocks binding of Mn2+treated MLN lymphocytes to
purified ICAM-1; however,
L11 fails to block binding to either ligand.
[View Larger Version of this Image (0K GIF file)]
Fig. 5.
L11 antigen is CD43. L11 (left), but not control mAb (right),
stained CD43-transfected CHO-P cells. CHO-P cells were transfected with mouse CD43 or mouse MAdCAM-1 cDNA and stained with L11
mAb or control mAb MECA367 (anti-mouse MAdCAM-1). MECA367
recognized MAdCAM-1 transfectants (not shown) but failed to stain
CD43 transfectants (right). L11 stained CD43 transfectants (left), but not
MAdCAM-1 transfectants (not shown).
[View Larger Version of this Image (0K GIF file)]
Fig. 6.
L11 antigen on T cells is CD43. LN lymphocytes preincubated with L11, anti-CD43 mAb S7, anti-CD44 mAb MJ64, control
mAb 9B5, or buffer were stained with FITC-labeled S7 or MJ64 and
their fluorescence measured by FACS® analysis. The x-axis is log10 fluorescence; mean fluorescence is indicated on each histogram. L11 blocked
FITC-S7 binding but not control mAb (FITC-MJ64) binding to T cells.
[View Larger Version of this Image (0K GIF file)]
Address correspondence to Dr. Leslie M. McEvoy, Department of Pathology, L235, Stanford University, Stanford, CA 94305.
Received for publication 6 November 1996 and in revised form 21 February 1997.
L.M. McEvoy was a Senior Fellow of the American Heart Association, California Division, and the National Multiple Sclerosis Society during part of this work. H. Sun is supported by a predoctoral award by the National Cancer Institute. This work was supported by grant AI37319 from the National Institutes of Health and the Core Facilities of the Stanford Digestive Disease Center under DK38707.The authors thank Evelyn Resurrecion, Jamie Lopez, Jean Jang, and June Twelves for technical assistance and Drs. Ellen Berg, Eddie Bowman, Carlo Laudanna, and Sherry Haugejordan-Brown for comments on the manuscript.
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