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,*
*
University of Alabama, Birmingham, AL 35294; and
Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4ß7-integrin. We studied in humans whether
intestinal T cells entering the blood upon antigenic activation would
exhibit homing commitments to the gut. Volunteers were immunized with
keyhole limpet hemocyanin (KLH) first orally and then parenterally or
only parenterally, and the expression of
4ß7 on T cells specific for KLH or tetanus
toxoid was studied. Circulating T cells were depleted of
4ß7+ cells by immunomagnetic
selection. This depletion removed a significant proportion of the
KLH-specific cells (mean decrease in proliferative response of 71%) in
the orally immunized volunteers. No difference in the KLH-induced
proliferation was found between the total and the
4ß7-depleted populations in volunteers
parenterally immunized with KLH, regardless of whether a preceding
mucosal priming had taken place or not. In both immunization groups,
the depletion of 4ß7+ cells
had no influence on the proliferative response to tetanus toxoid. We
conclude that, in contrast to T cells activated by parenteral
immunization, gut-derived T cells have preferential homing commitments
to the gut. This commitment was no longer observed after a subsequent
parenteral Ag administration. Besides showing that the site of Ag
encounter determines the expression of homing receptors, the present
study is the first to provide evidence for a circulation of newly
activated Ag-specific intestinal T cells back to the gut in
humans. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The homing of lymphocytes into tissues occurs in specialized
postcapillary high endothelial venules (18, 19, 20, 21). It is a multistep
process: a central event is the adhesion of lymphocyte surface homing
receptors (HRs)3 to their
counterparts, addressins, on endothelial cells. Because certain of the
addressins are distributed in a tissue-restricted manner,
tissue-specific homing of cells with the corresponding HR can occur.
Some HRs have been identified: 4ß7 guides
cells to the gut lamina propria (22, 23, 24), L-selectin to peripheral
lymph nodes (25, 26, 27, 28, 29), and cutaneous lymphocyte Ag to the skin (30, 31).
It has been shown recently in humans that, in contrast to parenterally
induced Ab-secreting cells, mucosally induced circulating Ab-secreting
cells all express the gut HR, 4ß7 (10).
This B cell commitment to home to the gut is direct evidence for the
recirculation of these cells to the gut in humans. On the basis of
these results, we set out to examine the homing potentials of
Ag-specific T cells after mucosal or parenteral immunization with a
previously unencountered Ag.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 19 healthy volunteers (10 women, 9 men, aged 22–40 years) participated in the study. None of the volunteers had been exposed previously to keyhole limpet hemocyanin (KLH); all of them had received the tetanus toxoid (TT) vaccine according to the usual vaccination protocol as a child and a booster dose within the last 10 years. The study was approved by the Human Use Committee of the University of Alabama at Birmingham. Informed consent was obtained from each volunteer before participation.
Experimental design
A total of 14 fasting volunteers ingested 100 mg of KLH on days
1–5 and days 15–19 (group A); 12 of them received 100 µg KLH s.c.
on days 26 and 36 (Fig. 1
A).
Another five volunteers received only the parenteral KLH on days 26 and
36 (group B). Blood samples were drawn on days 0, 26, and 44.
Mononuclear cells were isolated from the blood samples, and from these,
CD4 and CD8 cells were separated with immunomagnetic selection or T
cells were enriched with SRBC rosetting. From these cell populations,
4ß7-expressing cells were depleted with
immunomagnetic methods; the depleted as well as the total population
were assayed for KLH- or TT-reactive T cells with the proliferation
assay (Fig. 1B).
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KLH as a freeze-dried powder was purchased from Calbiochem (La Jolla, CA). For oral use, 100 mg of this preparation was packed into gelatin capsules. KLH for parenteral use was purchased from Pacific Biomarine (Venice, CA). It was purified from an ammonium sulfate preparation of protein. This preparation was dissolved in pyrogen-free saline, passed twice through a polymyxin-agarose column, and assayed for endotoxin content with Limulus assay as described previously in detail (16).
Isolation of mononuclear cells
Mononuclear cells were isolated with Ficoll-Paque density-gradient centrifugation from heparinized venous blood. The cells were washed twice with PBS and suspended in culture medium (RPMI 1640 supplemented with 10% heat-inactivated AB serum, 100 U penicillin/ml, and 100 mg streptomycin/ml).
Isolation of T cell-enriched population
The concentration of mononuclear cells was adjusted to 105 cells/ml. A T cell-enriched fraction was prepared by rosetting PBMCs with 2-aminoethylisothiuronium bromide-treated SRBCs (32) overnight on ice and subjecting them to density-gradient centrifugation on Ficoll-Paque. Cells at the plasma-Ficoll interface were removed (E- cells), and the T cell-enriched fraction (E+ cells) was prepared by hypoosmotic lysis of the SRBCs (33). Our earlier studies (16) show that the E+ fraction prepared with this method typically contains 60–80% of the total number of cells; the E- fraction contains 40–50% monocytes as measured by an esterase stain. E- cells were irradiated at 3000 rad before being used as APCs in culture.
Isolation of CD4+ and CD8+ cells
CD4+ and CD8+ cells were isolated from the mononuclear cells by immunomagnetic techniques. The concentration of mononuclear cells was adjusted to 8 x 106 cells/ml, and the cells were divided into aliquots. Magnetic beads coated with murine mAb specific for human CD4 (Dynabeads M-450 CD4; Dynal, Oslo, Norway) or CD8 (Dynabeads M450 CD8) were washed five times with the culture medium and added to the cell aliquots at a bead to target cell ratio of 4:1. The suspensions were incubated on ice for 30 min, with gentle shaking. The CD4+ or CD8+ cell populations were separated by applying a magnet outside the test tube and removing the supernatant containing the cells lacking the marker. The beads with the attached CD4+ or CD8+ cells were washed three times with culture medium and suspended in culture medium. The attached beads were removed from the positively selected cells by adding Detachabead (Dynal) solution and incubating with gentle shaking at room temperature for 1h. The cells were washed and resuspended in culture medium at a concentration of 104 cells/ml. The efficacy of the separation was determined by fluorescent Ab staining and flow cytometry.
Depletion of 4ß7+ cells
The 4ß7+ cells present
among enriched T cells or isolated CD4+ or CD8+
cells were depleted with immunoenzymatic techniques as described
previously in detail (9, 10). In brief, the cells were incubated with
the mAb to 4ß7, ACT-1 (LeukoSite,
Cambridge, MA) (34), at a concentration of 104 cells/ml for
30 min. The cells were then washed twice with the culture medium.
Magnetic beads coated with sheep Ab to murine Ig (Dynal) were washed
five times and incubated with the cells at a bead to target cell ratio
of 20:1. A magnet was applied outside the test tube, and the
supernatant with the negatively selected cells was collected. To remove
the possible contaminating
4ß7- cells, the beads with
the positively selected cells were washed two times, and the resulting
supernatants were pooled to the original population of negatively
selected cells (i.e., the 4ß7-depleted
cell population). The efficacy of the depletion was checked by
fluorescent Ab staining and flow cytometry.
Purity of separated cell populations
The E+ cells and the positively selected
CD4+ and CD8+ populations as well as the
negatively selected 4ß7-
population were analyzed for their expression of the various cell
surface markers with fluorescent Ab staining and flow cytometry
(FACStar; Becton Dickinson, San Jose, CA). The staining has been
described previously in detail (10). The mAbs used were phycoerythrin
(PE)-conjugated anti-CD3, anti-CD4, and anti-CD8 (all from
Becton Dickinson) and the nonlabeled
anti-4ß7 mAb, ACT-1, followed by a
FITC-labeled goat F(ab')2 anti-mouse Ab (Tago,
Burlingame, CA).
T cell-proliferation assay
Sterile 96-well microtiter plates (Costar, Cambridge, MA) were
used for cell culture. Triplicate wells were prepared with adherent
APCs by incubating 100 ml of 106 E- cells/ml
for 2 h. The wells were washed once with medium, and the T
cell-enriched (E+) cells or
4ß7-depleted E+ cells
(E+4ß7-) were
added at 2 x 106 cells/ml. Replicate wells received
10 mg/ml KLH, 1 mg/ml TT (purified TT was kindly provided by Dr.
Patricia J. Pietrobon, Connaught Laboratories, Swiftwater, PA), 2 mg/ml
PHA (Sigma, St. Louis, MO) as a positive control, or medium alone as a
negative control. The plates were incubated at 37°C and 5%
CO2 for 5 days. The wells were then pulsed with
[3H]thymidine (Amersham, Arlington Heights, IL) at 0.5
µCi/well for 6 h and harvested on nylon filters; cpm were
measured with a liquid scintillation counter. The results were
expressed both as 
cpm (i.e., the mean KLH- or TT-stimulated cpm
minus the mean unstimulated cpm) and as a stimulation index (SI) (i.e.,
the ratio of the mean of KLH- or TT-stimulated cpm divided by the mean
unstimulated cpm).
Statistical methods
The cpm and SI values of the total and
4ß7-depleted cell populations were
compared using the Wilcoxon nonparametric test for paired samples.
Because testing 4ß7 expression among
KLH-specific T cells is impossible in volunteers in whom no
KLH-specific T cells are found, only volunteers responding to KLH were
included in the statistical analysis. A volunteer was regarded as a
responder when the KLH-induced proliferation assay reached an SI of >3
or a cpm of >1000 on day 26 (orally immunized group, i.e., group A)
or day 44 (group receiving KLH only parenterally, i.e., group B).
Volunteers with an SI of >3 or a cpm of >1000 in preimmune samples
were regarded as responders only if a further increase of an SI of >3
or a cpm of >1000 was found postimmunization.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4ß7 was studied on
the surface of Ag-specific T cells from the peripheral blood of orally
(KLH) and/or parenterally (KLH, TT) immunized individuals by comparing
the proliferative activity of Ag-stimulated cell cultures of the
population of T cells, CD4+ cells, or CD8+
cells with those of the respective
4ß7-depleted populations. For the first
three volunteers, a T cell enrichment with SRBCs as well as CD4 and CD8
cell separations were conducted before 4ß7
separation. Because the CD8 population failed to proliferate after the
addition of either of the two Ags, and the proliferation in the CD4
population was similar to that in the T cell-enriched population, no
CD4 separation was conducted in the later experiments.
KLH- and TT-specific T cell proliferation was assessed before (day 0)
and after (day 26) KLH feeding and after parenteral KLH immunization
(day 44) (Fig. 1
). Even though none of the volunteers had been
immunized previously with KLH, three of them showed proliferative
activity already by day 0 (SI of >3 or cpm of >1000), probably due
to cross-reactivity with some other Ags previously encountered. To be
interpreted as a responder, these volunteers were required to have a
further increase of an SI of >3 or a cpm of >1000
postimmunization.
A response to KLH (see Materials and Methods for criteria)
was found in 10 of 14 volunteers after oral KLH immunization (group A),
in 12 of 12 volunteers after oral KLH followed by parenteral KLH, and
in 4 of 5 volunteers after parenteral KLH administration alone (group
B) (Fig. 2).
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4ß7-expressing cells was checked by
FACS. The CD4+ and CD8+ cell populations were
found to contain 97–99% or 95–97% CD4+ or
CD8+ cells, respectively. Depletion of the
4ß7-expressing cells was found to remove
most of the brightly staining cells (Fig. 3).
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cpm and SI values of proliferation to KLH were compared
between the E+ cells and the
4ß7-depleted E+ cells, the
latter were found to have significantly lower activity than the former
after the administration of oral KLH only (group A, day 26)
(p < 0.01 for both cpm and SI, Fig. 4A). No difference was found
between the two cell populations in their proliferative activity to TT.
The average decrease in the proliferative activity (cpm) following
the depletion of 4ß7+ cells
was 70.7% and 7.0% for KLH and TT, respectively
(p < 0.01). This significant decrease in the
proliferative activity to KLH was no longer found in the same
volunteers after the subsequent parenteral KLH immunization (group A,
day 44) (Fig. 5). Similarly, in
volunteers who received KLH only parenterally, no difference in the
proliferative activity to KLH or to TT was found between the
E+ and
E+4ß7- cell
populations (Fig. 4B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experiments performed in animals indicate that mucosally activated
lymphocytes migrate preferentially to mucosal sites (2, 3, 4, 5, 12, 13, 14).
Homing to the intestinal lamina propria has been shown to be mediated
by 4ß7-integrin on lymphocyte surface
binding to its vascular ligand, MAdCAM-1 (22). In the present study, a
significantly higher proportion of mucosally primed T cells compared
with parenterally primed T cells were found to express
4ß7, the gut HR. This finding demonstrates
that the expression of HRs depends upon the site of Ag encounter: T
cells primed at the gut mucosa have a higher commitment to home to the
gut. This observation suggests that a recirculation of newly activated
mucosal T lymphocytes to the mucosa occurs in humans.
Our results are consistent with studies suggesting that the site of Ag
encounter determines the homing phenotype of memory and effector T
cells in general (21, 36, 37). The findings are also in accord with a
recent study by Rott et al. (38) showing that T cells with immunologic
memory to rotavirus, an intestinal pathogen, belong to the
4ß7high T cell population.
Another Ag-specific T cell population expressing
4ß7 has been identified by Paronen et al.
(39): T cells reactive to an islet cell Ag in human insulin-dependent
diabetes mellitus express 4ß7, suggesting
a link between the gut immune system and autoimmunity against
pancreatic islets. However, the present study is the first to
demonstrate with a newly introduced Ag that the site of Ag encounter
determines the HR expression of the effector T cells in the blood.
Because exactly the same Ag was introduced to the body through the
parenteral route, the possible effect of differences in the nature of
the Ag is excluded.
Recently, it was reported that all of the mucosally induced B cells
expressed 4ß7 after oral immunization with
typhoid vaccine (10). Similar to those results, in the present study
with T cells, all of the mucosally activated T cells in 5 of 10
KLH-reactive subjects could be regarded as belonging to the
4ß7-expressing cell population (as judged
by an SI of <3 in the 4ß7-depleted
population). However, some reactivity was found among the
4ß7-depleted cells as well (2) in 5 of 10
subjects (1). Consistent with this observation, a similar low Ag
reactivity in the 4ß7- cell
population was found in three of five volunteers in a study on memory T
cells specific for rotavirus (38). A corresponding reactivity to a
mucosal Ag found among 4ß7- T
cells in some individuals has not been found among B cells, and may
therefore suggest a less restricted targeting of T cells to the site of
Ag priming compared with B cells.
One difference between this study and previous ones that have used
bacterial, viral, or vaccine Ags is that the feeding of protein Ags
such as KLH has been shown to induce oral tolerance rather than
immunity. Indeed, we have shown previously (16) that oral tolerance,
which is seen as a reduced responsiveness to parenteral immunization
following oral Ag administration, can be induced with an experimental
design similar to the one used in the present study (KLH orally plus
s.c.). In the present study, the mean cpm after s.c. KLH (group B,
Fig. 4B) was 20,114 compared with 9,896 after oral plus s.c.
KLH (group A, Fig. 5), which is consistent with the induction of oral
tolerance in the present study also. However, the statistical analysis
failed to show significance, most likely because the interindividual
variation between the magnitude of the responses would have required
larger groups to be analyzed when comparing groups with one another (as
opposed to comparisons between cell populations of the same individual
as done in the present study). In that previous study (16), the
peripheral blood T cells obtained after Ag feeding proliferated when
restimulated with KLH in vitro, even though those individuals were
subsequently found to have been tolerized by the feeding. Taken
together with the present results, it appears that the bulk of those
Ag-responsive T cells in the peripheral blood after Ag feeding bear the
gut HR. This observation suggests that there may be a phase of T cell
cycling back to the gut during the induction of oral tolerance.
Interestingly, the high proportion of
4ß7-expressing cells among the orally
induced KLH-specific T cells was not found in the same volunteers after
the subsequent administration of KLH through the parenteral route (Fig. 5). Hence, it seems that the subsequent parenteral immunization breaks
the mucosal homing commitment of the cells. However, it has not been
ruled out that the 4ß7-expressing cells
are simply overshadowed by a new set of naive T cells being stimulated
in the periphery by the subsequent parenteral immunization. The true
cause of the decrease in the
4ß7-expressing cells needs to be verified
in additional experiments (e.g., CD45RA/RO analysis of the cells). If
the mucosal homing phenotype is indeed broken by a subsequent
parenteral immunization, it would have practical consequences: the
targeting of an immune response in the body needs to be considered when
developing effective vaccines.
The possibility that there are qualitative as well as quantitative
differences in 4ß7 expression between the
orally and parenterally activated cell populations remains. The
separation process removed most of the
4ß7high staining cells (Fig. 3). This finding, combined with the data from the proliferation assay
of the same cell populations, indicates that most of the orally induced
T cells belong to the brightly staining
4ß7high cell population,
whereas only a smaller proportion of the parenterally induced T cells
belonged to this population. However, because the separation process
did not remove most of the very weakly staining cells, it is possible
that some of the parenterally induced T cells belonged to this cell
population. Hence, the results may simply indicate that orally induced
T cells express significantly more 4ß7
than parenterally induced T cells, which still bears the implication
that the former cells migrate more efficiently into the gut lamina
propria.
In conclusion, the present study provides evidence that the targeting of the Ag-specific human T cell response depends upon the site of Ag encounter. Oral administration of an Ag is followed by a response of circulating Ag-specific T cells with increased homing commitments to the gut lamina propria; this commitment is no longer observed after a subsequent parenteral Ag administration. The mucosal homing commitment of intestinally stimulated T cells supports the concept that the recirculation of newly activated mucosal T cells back to the mucosa occurs in humans.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Anu Kantele, Central Hospital of Central Finland, Keskussairaalantie 19, FIN-40630 Jyväskylä, Finland. E-mail address:
3 Abbreviations used in this paper: HR, homing receptor; KLH, keyhole limpet hemocyanin; TT, tetanus toxoid; PE, phycoerythrin; SI, stimulation index.
Received for publication July 17, 1998. Accepted for publication February 10, 1999.
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References |
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-interferon-mediated down-regulation of electrolyte secretion by intestinal epithelial cells: a local immune mechanism?. Scand. J. Immunol. 30:499.[Medline]
4ß7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74:185.[Medline]
4ß7, on human leukocytes. J. Immunol. 153:517.[Abstract]
4 integrins in lymphocyte homing to mucosal tissues in vivo. J. Immunol. 152:3282.[Abstract]
4ß7 by circulating CD4+ cells with memory for intestinal rotavirus. J. Clin. Invest. 100:1204.[Medline]
4ß7-integrin. Diabetes 46:583.[Abstract]
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