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Differential Homing Commitments of Antigen-Specific T Cells After Oral or Parenteral Immunization in Humans¹

Anu Kantele^2,,*, Jan Zivny^*, Miikka Häkkinen^*,, Charles O. Elson^* and Jiri Mestecky^*

^* University of Alabama, Birmingham, AL 35294; and Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland

	Abstract

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Animal experiments show that lymphocytes activated in the intestine circulate through mesenteric lymph nodes, lymphatics, and blood, returning to the gut. Homing into intestinal lamina propria is mediated by lymphocyte surface homing receptors, mainly the 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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Experiments performed in animal models have shown that orally administered Ags can activate intestinal lymphocytes, which migrate from intestinal inductive sites such as Peyer’s patches to mesenteric lymph nodes and then return via the lymphatics and blood to the intestinal lamina propria and to other mucosal sites such as salivary and mammary glands (1). This migratory behavior has been documented mostly for mucosal B cells in animals (2, 3, 4, 5); however, direct evidence for the recirculation of mucosal B cells in humans has emerged recently (6, 7, 8, 9, 10, 11). Documentation of a similar recirculation of activated mucosal T cells has been sparse. Adoptive cell transfer experiments have shown that under certain conditions, T cell blasts from mesenteric lymph nodes preferentially repopulate the gut upon transfer to syngeneic recipients (12, 13). Moreover, it has been shown that Ag-specific Th cells arising in the Peyer’s patches after intraPeyer’s patch immunization subsequently appeared in the thoracic duct, the intestinal epithelium, and the lamina propria of the gut (14). Consistent with this finding, it has been shown that the oral administration of an Ag gives rise to Ag-specific T cells in human peripheral blood (15, 16, 17). The aim of the present study was to investigate whether mucosally activated T cells, which are known to play an important role in controlling B cell proliferation and differentiation, would display similar migratory properties in humans (i.e., homing to the gut).

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.

	Materials and Methods

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Volunteers

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. 1A). 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).

View larger version (26K): [in this window] [in a new window]   FIGURE 1. Experimental design of the study. A, Protocol for immunization with KLH and for collection of blood samples. B, Assaying T cell proliferative activity to KLH and TT from the blood samples. For the first three volunteers, both the T cell enrichment with SRBCs and the CD4+ and CD8+ cell separations were conducted. In the remaining volunteers, only the T cell approach was used, because it was found to provide data similar to those obtained with CD4+ separation; CD8+ cells failed to proliferate.

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.

	Results

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The expression of 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).

View larger version (21K): [in this window] [in a new window]   FIGURE 2. KLH-induced proliferation of peripheral blood T cells. Data are shown as cpm for (A) all 14 vaccinees in group A on day 0 before the study (mean 556) and on days 26 (after oral feeding of KLH; mean 3670) and 44 (after s.c. injections of KLH; mean 13740) and for (B) all 5 vaccinees in group B on days 26 (preimmune; mean 463) and 44 (after s.c. injection of KLH; mean 16206).

View larger version (18K): [in this window] [in a new window]   FIGURE 3. Fluorescence-activated flow cytometric analysis of the depletion of 4ß7-expressing cells from peripheral blood T cells (SRBC-rosetted PBMCs = E+ cells) in a representative volunteer. E+ cells were stained with an irrelevant mAb of matching isotype (A) or with mAb to CD4 (PE) and 4ß7 (ACT-1) (FITC) (B); in addition, E+ cells were depleted from 4ß7+ cells with immunomagnetic separation and stained with mAb to CD4 (PE) and 4ß7 (FITC) (C).

View larger version (20K): [in this window] [in a new window]   FIGURE 4. KLH- and TT-induced proliferation of peripheral blood T cells (black bars) and 4ß7-depleted T cells (hatched bars) in volunteers after the administration of KLH perorally (group A, day 26, n = 10) (A) or s.c. (group B, n = 4) (B). Data are presented as the arithmetic mean of the cpm ± SE values of the responders. The respective SI values are shown under each bar. A statistical comparison between the E+ and E+4ß7- populations was conducted with the Wilcoxon nonparametric test for paired samples; the results are shown above the error bars (**, p < 0.01). In group A, the mean unstimulated cpm ± SE was 356 ± 122 and 197 ± 32 for E+ and E+4ß7- populations, respectively. In group B, the respective values were 434 ± 173 and 306 ± 137.

View larger version (17K): [in this window] [in a new window]   FIGURE 5. KLH-induced proliferation of peripheral blood T cells (black bars) and 4ß7-depleted T cells (hatched bars) in eight volunteers (group A) after the administration of KLH first perorally (day 26) and subsequently s.c. (day 44). Data are presented as the arithmetic mean of cpm ± SE values. The respective SI values are shown under each bar. A statistical comparison between the E+ and E+4ß7- populations was conducted with the Wilcoxon nonparametric test for paired samples; the results are shown above the error bars (**, p < 0.01). After peroral immunization, the mean unstimulated cpm ± SE was 334 ± 144 and 168 ± 30 for E+ and E+4ß7- populations, respectively. After s.c. immunization, the respective values were 837 ± 343 and 306 ± 94.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

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 ₄ß₇^high 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 ₄ß₇^high 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 ₄ß₇^high 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.

	Footnotes

 
¹ This work was performed at the University of Alabama, Birmingham, AL. It was supported by National Institutes of Health Grant AI 35991, by the Finnish Academy, and by the Maud Kuistila Foundation.

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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