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* Burns and Allen Research Institute and Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048;
Univerity Hospital of Heraklion, University of Crete, Heraklion, Crete, Greece; and
Millennium Pharmaceuticals, Cambridge, MA 02139
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Abstract |
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and IL-10. IL-10-producing cells were exclusively detected within the CCR9+ subset of CD4+ T cells by intracellular staining and were distinct from IL-2- and IFN--producing cells. Moreover, memory CCR9+CD4+ lymphocytes respond to CD2 stimulation with proliferation and IFN-/IL-10 production, whereas memory CCR9-CD4+ cells were unresponsive. In addition, memory CCR9+CD4+ T cells support Ig production by cocultured CD19+ B cells in the absence of prior T cell activation or addition of exogenous cytokines. Our data show that the memory subset of circulating CCR9+CD4+ T cells has characteristics of mucosal T lymphocytes and contains cells with either Th1 or T-regulatory 1 cytokine profiles. Studies on the cytokine profile and Ag specificity of this cell subset could provide important insight into small intestinal immune-mediated diseases and oral tolerance in humans. |
Introduction |
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4
7+-intestine-homing lymphocytes (18, 19, 20, 21). These data suggest an important role of certain chemokines and their receptors in regulating the homing of specific T cell subsets into microanatomic compartments of lymphoid organs and peripheral tissues (4).
We and others have proposed that the chemokine thymus-expressed chemokine (TECK)/CCL25 and its receptor CCR9 may play an important role in the regional specialization of intestinal immunity and that the combined expression of CCR9 and 47 on the cell surface may provide a small intestinal address code for circulating intestinal memory T cells (20, 21). CCR9 is expressed on a small subset of PB CD4+ (2–4%) and CD8+ T cells, most of which coexpress the mucosal homing ligand 47 (18). Here, we show that circulating CCR9+CD4+ T cells from normal donors have characteristics of mucosal T cells in terms of an activated phenotype, proliferative response to anti-CD2 stimulation, a Th1 or T-regulatory 1 (Tr1) cytokine profile, and support for Ig production by cocultured B cells. This T cell subset may provide a peripheral window to small intestinal immunity in humans and a tool to study Ag specificity and cytokine profile of effector and regulatory cells in small bowel inflammatory diseases and in oral tolerance.
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Materials and Methods |
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Anti-CD3, -CD4, -CD8, -HLA-DR dye-linked mAbs for immunofluorescence studies were obtained from Caltag (Burlingame, CA). Anti-CD25, -CD69, -7 integrin, -CD40L, -OX-40, -CTLA, -CD27, -CD71, -CD62L, and -CD45RO dye-linked mAbs were obtained from BD PharMingen (San Diego, CA). The PE- or FITC-conjugated anti-cytokine Abs to IFN-, IL-4, and IL-10 were from BD PharMingen. The FITC-conjugated anti-IL-2 Ab was from Caltag. PWM was from Sigma-Aldrich (St. Louis, MO). The anti-CCR9 mAb, 3C3, was from Millennium Pharmaceuticals (Cambridge, MA).
Cell isolation, sorting, and FACS analysis
PBLs were isolated from normal healthy volunteers by separation on Ficoll-Hypaque gradients. The cells were subsequently washed three times with HBSS and resuspended in RPMI 1640 containing 2 mM L-glutamine, 1% nonessential amino acids, 1% sodium pyruvate, 50 µg/ml penicillin-streptomycin, and 10% heat-inactivated FCS. The cells were stained with anti-CCR9 mAb (3C3, IgG2b) followed by a secondary PE- or tricolor (TC)-conjugated goat anti-mouse IgG2b mAb (Caltag). The cells were washed and incubated with mouse IgG for 15 min and subsequently stained with FITC-conjugated anti-CD4 mAb. After staining, the cells were sorted using FACSVantage (BD Biosciences, San Jose, CA) to isolate CD4+CCR9+ and CD4+CCR9- cells (purity, >99%). In some experiments, cells were stained with anti-CCR9/TC-conjugated goat anti-mouse IgG2b mAb, PE-conjugated anti-CD45RO, and FITC-conjugated anti-CD4 mAb and sorted into CD4+CD45RO+CCR9+, CD4+CD45RO-CCR9+, and CD4+CD45RO+CCR9- cells (purity, >98%).
For staining of cell surface Ags, 5 x 10 5 freshly isolated PBL were washed twice with PBS supplemented with 0.1% BSA and 0.1% azide and resuspended in 100 µl of 10% human Ab serum to block nonspecific Fc binding for 15 min. The cells were incubated with the anti-CCR9 mAb 3C3 for 30 min on ice, washed with PBS-BSA-azide, and incubated with a secondary goat anti-mouse IgG2b-TC for 30 min on ice. The cells were washed again with PBS-BSA-azide and incubated with mouse IgG for 15 min. FITC- and PE-conjugated mAb for surface Ag were used for 30 min. After two washings, cells were resuspended in 400 µl of 1% paraformaldehyde in PBS and analyzed by FACS (BD Biosciences, San Jose, CA); 3 x 104 events were routinely collected and analyzed using CellQuest software (BD Biosciences).
Cytokine detection
Sorted CD4+CCR9+ and CD4+CCR9- T cells or CD4+CD45RO+CCR9+, CD4+CD45RO-CCR9+, and CD4+CD45RO+CCR9- cells were stimulated with plate-bound anti-CD3 (OKT3, 1 µg/ml; American Type Culture Collection, Manassas, VA) with or without soluble anti-CD28 (clone 9.3, 2 µg/ml) or with soluble anti-CD2 Abs (clones CB6 and GD10 at 1 µg/ml, a gift from C. Benjamin, Biogen, Cambridge, MA) with or without anti-CD28, and cytokine production was measured in the 24- and 72-h culture supernatants by ELISA using matched pairs of Abs specific for IL-10 and IFN-. For cytokine detection at the single-cell level, sorted CD4+ T cell subsets were stimulated with 50 ng/ml PMA (Sigma) and 1 µg/ml ionomycin for 5 h. Brefeldin A (10 µg/ml) was added to the culture after 2 h of stimulation to block cytokine secretion. Cells were fixed and permeabilized using Cytofix-Cytoperm solution (Caltag) and stained with PE- and FITC-conjugated control Abs or mAbs to IL-2, IFN-, IL-4, and IL-10.
Proliferation assays
Sorted CD4+CCR9+ and CD4+CCR9- T cells or CD4+CD45RO+CCR9+ and CD4+CD45RO+CCR9- cells were stimulated with plate-bound anti-CD3 (1 µg/ml) with or without soluble anti-CD28 (2 µg/ml) or with soluble anti-CD2 (1 µg/ml) with or without anti-CD28 and pulsed with 1 µCi/well [3H]thymidine for the last 16 h of a 96-h culture. Radioactivity was analyzed on a scintillation counter.
Ab production
PB T cells (CD4+CD45RO+CCR9+ or CD4+CD45RO+CCR9-) and B cells (CD19+) were sorted by FACS and cocultured in round-bottom 96-well plates at 105 cells/well each of T and B cells in the absence of T cell activation stimuli or cytokines for 11 days. B cells stimulated with PWM (5 µg/ml) were used as positive control. IgM, IgG, and IgA contents in the culture supernatants were determined by ELISA.
Statistical analysis
Differences between the percentage of phenotypic markers expressed between CCR9+ and CCR9- T cells were compared with a paired t test. p < 0.05 was considered statistically significant.
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Results |
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We have recently shown that patients with small intestinal inflammatory diseases, such as Crohn’s and celiac disease, have a higher percentage of circulating CCR9+CD4+ T cells than do patients with colonic Crohn’s or normal healthy donors; therefore, this cell subset is potentially involved in these small intestinal inflammatory processes. To gain insight into the functional aspects of the CCR9+ PB T cells from normal donors, we first examined the expression of several activation markers and costimulatory molecules on CCR9+ PB T cells. As shown in Fig. 1 and Table I, more CCR9+ T cells express CD4 and CD8 and the activation markers CD25, CD69, CD71, and HLA-DR than do CCR9- T cells. Similarly, the fraction of cells expressing OX-40 and CD40L was higher in CCR9+ than in CCR9- T cells. The CD27+ fraction was similar in the two cell subsets. Most CCR9+ and CCR9- T cells coexpress CD62L, but the positive fraction was lower for circulating CCR9+ compared with CCR9- T cells. Additionally, more CCR9+ T cells were CD45RO+ and 7 integrin+ as compared with the CCR9- T cells, as previously described (see also Fig. 1 and Table I). Collectively, our data show that a subset of circulating CCR9+ T cells have a phenotype associated with activation. Addition of CD4+ and CD8+ percentages of CCR9+ T cells gives >100% (see Fig. 1 and Table I), indicating that a subset of CCR9+ T cells must be double-positive T cells, which is consistent with their activation phenotype (22).
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To determine the activation requirement of PB CCR9+CD4+ T cells, sorted CD4+CCR9+ and CD4+CCR9- T cells were stimulated with IL-2, or anti-CD3 ± CD28, or anti-CD2 ± CD28, and proliferation of each cell subset was analyzed. As shown in Fig. 2A, CCR9+CD4+T cells were more responsive to IL-2 or anti-CD3 stimulation alone than were the CCR9-CD4+ T cells. Both CCR9- and CCR9+CD4+ T cells, however, proliferated when costimulated with anti-CD28 Abs. It has been previously shown that mucosal T cells differ from PB-derived T cells in that the former exhibit an activated phenotype yet, although proliferating poorly to anti-CD3 stimulation, show enhanced proliferation and cytokine secretion in response to CD2 activation (23). Because a subset of circulating CCR9+ T cells have an activated phenotype, express high levels of the mucosal homing ligand 7 integrin, and increase in frequency with small bowel inflammatory diseases, we tested the hypothesis that these cells preferentially respond to CD2 activation and therefore could potentially represent circulating mucosal T cells. As shown in Fig. 2A, CCR9+CD4+ T cells proliferated vigorously with anti-CD2 activation, whereas the CD4+CCR9- cells were unresponsive. Both subsets proliferated vigorously when costimulated with CD28. The CD2 responsiveness of the CCR9+CD4+ cells was present in highly purified memory (CD45RO+) cells, whereas the CD45RO+ subset of CCR9-CD4+ cells was unresponsive to CD2 stimulation (Fig. 2B). Therefore, the responsiveness of CCR9+CD4+ T cells to CD2 stimulation was not simply due to the higher percentage of memory cells contained within this cell subset compared with CD4+CCR9- T cells. The CD2 responsiveness of mucosal T cells compared with PB T cells, shown previously by our laboratory and others, is not simply the result of the memory T cell phenotype, but rather the result of unique activation requirements of mucosal T cells (23). These data suggest that PB memory CCR9+CD4+ T cells represent circulating mucosal T cells recently activated in vivo but not yet fully differentiated.
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We have previously shown that purified small bowel CCR9+ and CCR9- T cells exhibit a dominant Th1 cytokine profile and that the small percentage of Th2-producing cells were equally represented within the CCR9+ and CCR9- subset of small bowel T lymphocytes, suggesting that CCR9 expression is not linked to a Th1 or Th2 cytokine profile but rather to a phenotype with selective homing potential to the small bowel mucosa (21). To gain better insight into the cytokine production profile of circulating CCR9+CD4+ cells, we first examined IFN-, IL-2, and IL-4 production at the single-cell level by intracellular cytokine staining. We also studied the expression of IL-10, which is produced by mucosal T cells and implicated in immunological tolerance in the intestine. The percentage of IFN--producing cells was higher in CCR9+ than in CCR9-CD4+ T cells (Fig. 3, A and C), but there was no difference in the percentage of IL-4- or IL-2-producing cells among CCR9+CD4+ and CCR9-CD4+ T cells (Fig. 3, A and B). Interestingly, IL-10-producing CD4+ T cells were detected exclusively within the CCR9+ subset of CD4+ T cells (Fig. 3, B and C). Costaining of CCR9+CD4+ T cells for IFN- and -IL-10 showed that these cytokines are produced largely by distinct cell subsets (Fig. 3C). To confirm the cytokine profile of CCR9+ and CCR9-CD4+ T cells, we examined the production of IFN- and IL-10 in culture supernatant after stimulation with anti-CD3 ± CD28 Ab. Large amounts of IFN- and IL-10 were detected in the 24-h culture supernatant of CCR9+CD4+ T cells stimulated with anti-CD3 ± CD28 Ab (Fig. 4). IFN- was detected at lower levels in the supernatant of CCR9-CD4+ T cells, and IL-10 at much lower levels, compared with that in the supernatant of CCR9+CD4+ T cells (Fig. 4). Because CCR9+CD4+ T cells proliferate in response to CD2 stimulation, we examined whether they also produce cytokines when activated through the CD2 pathway. As shown in Fig. 4, large amounts of IFN- and IL-10 were detected in the supernatant of CCR9+CD4+ T cells after stimulation with CD2 ± CD28 Ab, whereas neither cytokine was detected in supernatant from CCR9-CD4+ T cells stimulated by CD2 ± CD28 Ab.
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and IL-10 production by anti-CD3 or -CD2 stimulated memory CCR9+ and CCR9-CD4+ T cells, and naive CCR9+CD4+ T cells (Fig. 5). Significantly more IFN- and IL-10 were detected in 24-h supernatant of memory CCR9+ than in memory CCR9- or naive CCR9+CD4+ cells (Fig. 5A). Similar results were obtained when we analyzed IFN- and IL-10 in 72-h culture supernatant (Fig. 5B). Interestingly, IL-10 was detected at 72 h for both memory CCR9- and naive CCR9+CD4+ cells, but only when cells were stimulated with both anti-CD3 and -CD28 Ab (Fig. 5B). CD2 ± CD28 stimulation induced detectable amounts of IFN- or IL-10 only by the memory subset of CCR9+CD4+ T cells (Fig. 5). The rapid production of IL-10 by CCR9+CD4+ T cells detected by intracellular staining and the detection of high levels of IL-10 in culture supernatants of memory CCR9+CD4+ T cells after only 24 h show that a subset of these cells rapidly produce large amounts of IL-10 early on, typical of Tr1 cells (24).
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We hypothesized that the cytokine profile and activated phenotype of PB CCR9+ T cells, including the expression of CD40L, would promote B cell activation, and Ig production (25, 26). Therefore, we analyzed the ability of sorted CCR9+CD4+ T cells to provide B cell help for Ab production in an in vitro assay (9, 10). Coculture experiments of memory CCR9+ or CCR9-CD4+ T cells with autologous PB CD19+ B cells in the absence of added T cell stimuli or exogenous cytokines showed that CCR9+CD4+ T cells are potent inducers of IgA, IgG, and IgM production (Fig. 6). B cells cultured alone or in the presence of CCR9-CD4+ T cells produced little Abs. Stimulation of B cells with PWM was the positive control for Ig production (Fig. 6).
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Discussion |
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TCR intraepithelial lymphocytes in the small intestine but more in colon and, surprisingly, normal numbers of small intestinal lamina propria lymphocytes in the small intestine and practically normal thymic T cell development (28, 29). Recent data also show that TECK/CCL25 plays an important role in the generation of murine cryptopatches and subsequent appearance of intraepithelial lymphocytes, localization of activated CD8+ lymphocytes to the small intestine, and chemoattraction of IgA-producing cells in vitro (30, 31, 32). In the current study, we analyzed the phenotype and effector function of the small subset of CCR9+ PB T cells from normal human donors. We hypothesized that this subset, especially the CD45RO+CCR9+ cells, represent circulating, recently activated mucosal T cells homing back to the small bowel lamina propria (33, 34). This idea is supported by the observations that CCR9+ PB T cells 1) contain high fractions positive for activation markers and costimulatory molecules, 2) respond to CD2 as well as to CD3 stimulation (the former a signature activation pathway of mucosal T cells), 3) contain both Th1 and Tr1 cells and 4) support Ig, including IgA, production by cocultured CD19+ B cells without additional T cell activation or added cytokines. The most substantial difference in the phenotypic marker expression between CCR9+ and CCR9- T cells was the high fraction expressing CD25, CD69, CD71, HLA-DR, and the costimulatory molecules OX-40 and CD40L in CCR9+ cells, consistent with a phenotype of activated T cells.
In addition, because CD2 responsiveness of freshly isolated T cells has been documented for those cells derived from the intestinal mucosa and because highly purified memory CCR9-CD4+ T cells were unresponsive to CD2 stimulation, the CD2 responsiveness of CCR9+CD4+ memory cells in blood strongly suggests that they are generated in the inductive sites of the mucosal immune system. Analysis of the effector function of circulating memory CCR9+CD4+ T cells revealed that they produce large amounts of IFN- or IL-10 promptly after in vitro stimulation and, therefore, contain differentiated Th1 and Tr1 cells. It is interesting that a similar cytokine profile, e.g., production of IFN- and IL-10, is seen for stimulated mucosal T cells (21, 35). Therefore, it is tempting to speculate that Th1 and Tr1 CCR9+CD4+ T cells are continuously generated in the inductive sites of the small intestinal mucosal immune system and play an important role in effector and regulatory functions in the intestine (36, 37). Further studies are required to characterize each cell subset within CCR9+CD4+ PB T cells.
Human and mouse Tr1 or Tr1-like cells have been generated in vitro after manipulation of T cells with cytokines or drugs or under certain stimulatory conditions with APC and costimulatory molecules (38, 39, 40, 41, 42, 43), but this is the first report to our knowledge that identifies cells with the characteristics of human Tr1 cells de novo, within freshly isolated PB T cells of normal donors, to be restricted to a specific T cell subpopulation. Groux et al. (38, 44) have shown that chronic activation of both human and murine CD4+ T cells in the presence of IL-10 gave rise to the development of CD4+ T cell clones with low proliferative capacity. This IL-10-mediated anergy was associated with induction of a population of Tr1 cells producing high levels of IL-10, low levels of IL-2, and no IL-4, which could suppress Ag-specific responses in vivo and in vitro (38). Activation of human CD4+ T cells with immature dendritic cells or anti-CD2-costimulated CD4+ T cells also led to the generation of Tr1 cells (39, 40). Barrat et al. (41) showed that repeated stimulation of human and murine naive CD4+ T cells in the presence of dexamethasone-1,25(OH)2-vitamin D3 and anti-Th1/Th2 polarizing cytokine Ab leads to the development of Tr1 cells as well. Kemper et al. (45) have recently shown that coengagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. How could CCR9+ Tr1 cells arise? Several mechanisms may operate in the small bowel mucosal immune system to induce and maintain CCR9+ Tr1 cells: 1) continuous exposure to dietary, commensal bacterial or other intestine-derived Ags may lead to the generation of Ag-specific Tr1 cells after these Ags are presented to naive T cells in draining lymph nodes by immature dendritic cells in the absence of costimulation; 2) acquisition of CD2 responsiveness of CCR9+CD4+T cells in the mucosa could further induce their differentiation into Tr1 cells (40) after recruitment into the lamina propria and interaction with CD58, which is expressed by mucosal B cells and intestinal epithelial cells (46). Further identification of the surface phenotype of CCR9+CD4+ IL-10-producing T cells from PB could provide important insight into the mechanism of generation of this T cell subset in humans and lead to new strategies for immunotherapy in small bowel inflammatory disease, such as Crohn’s disease.
One important functional aspect of memory CCR9+CD4+ T cells is their ability to support Ab production by cocultured B cells, including IgA, further supporting their mucosal origin. B cell helper activity for Ab production has been reported for tonsillar but not PB CXCR5+ T cells (9, 10, 47). The support for Ab production by cocultured B cells provided by memory CCR9+CD4+ T cells without added T cell stimulation is consistent with their activated phenotype, particularly their expression of CD40L and their ability to produce IL-10. We have detected, in some experiments, significant levels of IL-10 in 24-h culture supernatants of sorted memory CCR9+CD4+ T cells with no added T cell-activating agents (data not shown), suggesting that these cells have been recently activated in vivo before their isolation. We have not yet tested whether memory CCR9+CD4+ T cells simply stimulate Ig production by differentiated B cells, or induce differentiation and isotype switching by naive B cells, or both. Another explanation for the B cell helper activity of circulating memory CCR9+CD4+ T cells may lie in their responsiveness to CD2 signaling. B cells could further activate these T cells during culture through LFA-3/CD2 or LFA-1/ICAM-1 interactions (48), leading to up-regulation of CD40L expression, cytokine secretion, and efficient help for Ig production. Further studies are needed to test these possibilities.
Our data provide strong evidence that human PB memory CCR9+CD4+ T cells represent circulating intestinal mucosal T cells, which have been recently activated in vivo, possibly in Peyer’s patches and/or draining mesenteric lymph node. Because activation of naive CD4+ T cells in vitro in the presence of several cytokines, including IL-10 or TGF-, is not sufficient to induce CCR9 (18), its expression may require contact with specialized APC in the mucosal environment (49, 50). In mice, intestinal immunization with Ag leads to up-regulation of 47 and the acquisition of TECK/CCL25 responsiveness in intestinal lymph nodes by T cells (50). Therefore, the induction of CCR9 expression by T cells activated in the inductive sites of the mucosal immune system, with the concomitant generation of both inflammatory (Th1) and regulatory (Tr1) T cells, would enable the small intestinal mucosal immune system to mount protective immunity to pathogens and at the same time immune tolerance to dietary Ags and commensal bacteria. Undoubtedly, elucidation of the mechanism(s) of CCR9 induction in human T cells and of the requirements for generation of CCR9+ Th1 and Tr1 cells will provide important insights into human small intestinal immunity and its perturbations during inflammatory diseases, and form the basis for the development of novel therapeutics.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Konstantinos A. Papadakis, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, D-4063, Los Angeles, CA 90048. E-mail address: Papadakisk{at}cshs.org or Dr. Stephan R. Targan, 8700 Beverly Boulevard, D-4063, Los Angeles, CA 90048. E-mail address: Targans{at}cshs.org
3 Abbreviations used in this paper: PB, peripheral blood; CCL, C-C chemokine ligand; TECK, thymus-expressed chemokine; Tr1, T-regulatory 1; TC, tricolor.
Received for publication December 20, 2002. Accepted for publication April 18, 2003.
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: evidence for TGF- but not IL-10-dependent direct Sµ
S and sequential SµS, SS DNA recombination. J. Immunol. 161:5217.+ gut intraepithelial lymphocytes. Blood 98:2626.+ lymphocytes to the small-intestinal mucosa. J. Clin. Invest. 110:1113.[Medline]
and IL-10 induce the differentiation of human type 1 T regulatory cells. J. Immunol. 166:5530.This article has been cited by other articles:
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