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TGF--Producing CD4⁺ Mediastinal Lymph Node Cells Obtained from Mice Tracheally Tolerized to Ovalbumin (OVA) Suppress Both Th1- and Th2-Induced Cutaneous Inflammatory Responses to OVA by Different Mechanisms¹

Tadashi Terui^2,*, Kunio Sano, Hidekazu Shirota, Nagisa Kunikata^*, Maki Ozawa^*, Mikiko Okada^*, Motoko Honda^*, Gen Tamura and Hachiro Tagami^*

^* Department of Dermatology and First Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan

	Abstract

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Advances in the treatment of allergic disorders require elucidation of the autoregulatory immune systems induced in averting detrimental inflammatory responses against invading foreign Ags. We previously reported that excessive Ags intruding through the airway mucosa induce a subset of regulatory CD4⁺ T cells secreting TGF- in the regional mediastinal lymph nodes (MLNs), which inhibits Th2 cells and subsequent eosinophilic inflammation in the trachea. In the present experiments we examined whether and in what mechanisms TGF--secreting CD4⁺ T cells in the MLNs regulate Th cell-mediated skin inflammation using a previously established murine model. Th1 or Th2 cells injected s.c. into ear lobes of naive mice induced swelling, whereas the concomitant local injection of MLN cells suppressed the inflammation. The suppressor activities of MLN cells were markedly neutralized by anti-TGF- mAb and were mimicked by rTGF-. The MLN cell- and rTGF--induced inhibition was reversed by anti-IL-10 mAb significantly in Th1-induced inflammation and only partially in Th2-induced inflammation. rIL-10 reduced Th-induced ear swelling, although higher doses of rIL-10 were required in Th2-induced one. Thus, allergen-specific TGF--producing CD4⁺ T cells induced in the respiratory tract controlled cutaneous inflammatory responses by Th1 or Th2 cells either directly by TGF- or indirectly through IL-10 induction. From a clinical standpoint, these observations might explain the mechanism of spontaneous regression in some patients with atopic dermatitis, which exhibits both Th1- and Th2-mediated skin inflammation in response to airborne protein Ags.

	Introduction

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In healthy individuals, there are mechanisms to prevent induction of deleterious immune-mediated inflammatory responses against airborne allergens (1). Conversely, destructive mechanisms induced by airborne allergens mediate allergic diseases such as Th2-mediated bronchial asthma and allergic rhinitis, and both Th1- and Th2-associated atopic dermatitis (AD)³ (2, 3, 4). Patients with severe cases of these disorders can be treated with Ag-nonspecific immunosuppressants such as cyclosporin A, FK506, and glucocorticosteroids. Because these therapeutic agents sometimes cause adverse effects such as the deterioration of host immunologic defenses, however, an effective mechanism to selectively suppress Th1 and Th2 cell-mediated responses specific for relevant allergens is needed. One such specific immunotherapy for autoimmune or allergic diseases is the induction of Ag-specific peripheral tolerance.

Experimental evidence indicates that orally administered protein Ags can reduce autoimmune and allergic reactions. Hyporesponsiveness to Ags contained in ingested foods is known as oral tolerance and consists of two distinctive types, i.e., anergy and active suppression (5, 6, 7). In active suppression, suppressive cells obtained from orally tolerized animals exert their inhibitory effects through the production of TGF- (8, 9, 10, 11, 12).

In several animal models, the respiratory tract and nasal tissue are sites for the induction of Ag-specific peripheral tolerance mediated by different types of cells, i.e., IFN--producing CD8⁺ T cells (13, 14, 15) or Th2 cells (16, 17, 18, 19). More recently, our colleagues reported that TGF--producing mediastinal lymph node (MLN) cells obtained from mice tolerized to high-dose OVA regulated OVA-specific eosinophil-mediated bronchial inflammation (20). Together, these observations suggest that autoimmune or allergic reactions can be tolerized with tracheally administered protein Ags.

We previously succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein Ag-specific Th1 or Th2 cells (21). We also demonstrated that neutrophils or eosinophils are the major effector cells in Th1- or Th2-mediated cutaneous inflammation, respectively. In the present study using the animal model, we investigated whether MLNs from tracheally tolerized mice controlled cutaneous immunologic responses induced by either Th1 or Th2 cells. We here report that TGF--producing CD4⁺ MLNs ameliorate ear skin inflammation promoted by either Th1 or Th2 cells, and the MLNs exert these suppressive effects on Th-induced skin inflammation directly by TGF- and/or indirectly by its IL-10 induction.

	Materials and Methods

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Animals and adoptive transfer

Male BALB/c mice were bred in our animal facility and were used at 8–12 wk of age. BALB/c mice transgenic (tg) for TCR specific for OVA_323–339 (anti-OVA TCR tg mice) were established as described previously (22). Anti-OVA TCR tg mice were lightly anesthetized with pentobarbital (Abbott Laboratories, North Chicago, IL), and 500 µg of OVA (Sigma-Aldrich, St. Louis, MO) in 50 µl of PBS was instilled directly into the surgically exposed trachea to induce high dose tolerance. As reported by our colleague (20), adoptive transfer of MLNs from tolerant mice reduces eosinophil-mediated bronchial inflammation through the action of TGF-. After 7 days, 1 x 10⁶, or the indicated number of MLNs, were adoptively transferred s.c. or i.v. to naive BALB/c mice. Local s.c. injection of MLNs to the right ear lobes of the naive mice was conducted concomitantly with OVA-specific Th1 or Th2 cells in 50 µl of PBS in the presence of 100 µg/ml OVA. In contrast, 1 h after i.v. injection, each Th cell was injected into the ear lobes as well.

In vitro induction of Th1 and Th2 cells

Th1 and Th2 cells were prepared as described previously (21). Briefly, spleen cells (3 x 10⁷) from nonimmunized anti-OVA TCR tg mice were cultured for 3 days in 12 ml of RPMI 1640 medium with OVA (100 µg/ml) together with IL-12 (1 ng/ml; Genzyme, Cambridge, MA) for Th1 cells or IL-4 (10 ng/ml; Genzyme) plus anti-IL-12 mAb (0.1 µg/ml; Genzyme) for Th2 cells. The cells were then cultured in fresh medium without any cytokines or anti-cytokine Ab for an additional 3 days.

Enrichment of CD4⁺ or CD8⁺ T cells

Cells were preincubated with anti-I-A^d (MKD-6) mAb (23) plus either anti-CD4 (Gk-1.5) (24) or anti-CD8 mAb for 1 h at 4°C. They were allowed to react with anti-mouse Ig (Caltag Laboratories, San Francisco, CA) immobilized on plastic plates (Falcon, Lincoln Park, NJ) for 1 h at room temperature, and nonadherent cells were recovered as CD8⁺ or CD4⁺ T cells. Flow cytometry revealed a >90% depletion of Ia⁺, CD4⁺, or CD8⁺ cells. Each mAb was used at a 1/1000 dilution of the ascites form.

Neutralization of cytokines by mAbs

The right ear lobes of four to five naive BALB/c mice were injected s.c. with 0.3–3 µg/site of anti-TGF- mAb (mouse IgG1; Genzyme) or anti-IL-10 mAb (rat IgG1; BD PharMingen, San Diego, CA) with effector T cells. Mouse IgG1 or rat IgG1 Ab (BD PharMingen) served as respective isotype controls.

Ear swelling assay

Ear swelling induced by OVA-primed Th cells was evaluated as previously described (21). Briefly, 1 x 10⁶ cells were injected s.c. into the right ear lobes of naive, non-tg male BALB/c mice. A total of 50 µl of OVA-primed Th cell suspension was injected via a 1-ml syringe equipped with a 27-gauge x 1/2 needle. The left ear lobes were not treated. The thickness of each ear lobe was measured using a precision caliper (Mitsutoyo, Tokyo, Japan) immediately before and at various time periods after injection. Ear swelling was expressed as [(thickness of the right ear after injection - thickness of the left ear) - (thickness of the right ear before the injection - thickness of the left ear)] x 0.01 mm. Results are shown as the mean swelling ± SD. Suppression assays using blocking Abs were conducted twice, and other experiments were repeated at least three times. Each experimental group was comprised of four to five mice, unless otherwise stated. Determination of ear thickness was performed in a blinded fashion. Student’s t test was used for statistical analysis.

We also locally administered rTGF- that cross-reacts with murine TGF-1 or rIL-10 (R&D Systems, Minneapolis, MN) to evaluate its suppressive effects on Th-induced skin inflammation. We also checked the effects of irrelevant cytokines such as IL-3, IL-4, IL-18, and TNF- purchased from R&D Systems.

	Results

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MLNs from tolerized mice suppressed ear swelling induced by both Th1 and Th2 cells

Ear thickness started to increase 12 h after s.c. injection of 1 x 10⁶ cultured Th1 cells into the right ear lobes of naive BALB/c mice. The swelling reached a peak 48 h postinjection. In contrast, ear swelling in Th2-cell-injected mice was detectable at 6 h and became maximal at 24 h (Fig. 1). Ear thickness induced by either Th cell was not detected without addition of OVA. These findings confirmed our previous observations (21). The ear swelling induced by each Th cell was reduced by i.v. injection of MLNs from tracheally tolerized anti-OVA TCR mice. However, substantial numbers (3 x 10⁶) of MLNs were required to inhibit the ear swelling induced by 1 x 10⁶ Th1 or Th2 cells (Fig. 1). Neither MLNs nor control spleen cells alone induced ear swelling.

View larger version (18K): [in this window] [in a new window]   FIGURE 1. i.v. administered MLNs obtained from a tolerant mouse reduced ear swelling due to both Th1- and Th2-induced cutaneous inflammatory responses. Th1 or Th2 cells were prepared by short-term culture of splenocytes from anti-OVA TCR mice. MLNs were obtained from anti-OVA TCR mice given OVA intratracheally 7 days before this experiment (see Materials and Methods). MLNs obtained from tolerized mice were injected i.v. into naive BALB/c mice. Ear thickness in Th1-injected mice increased beginning at 12 h and reached a peak at 48 h postinjection. Ear thickness in Th2-injected mice was detectable at 6 h and was maximal at 24 h. Neither Th1 nor Th2 cells in the absence of OVA induced ear swelling. One hour after i.v. injection of the MLNs, Th1 or Th2 cells (1 x 106 cells/site) in 50 µl of PBS with OVA (100 µg/ml) were injected into the right ear lobes of naive mice. MLNs (3 x 106) reduced ear swelling induced by Th1 or Th2. i.v. injection of 3 x 106 control splenic cells from naive mice did not affect ear thickness, and neither MLNs nor control splenic cells influenced ear thickness alone. Sp, control splenocytes; OVA(-), without addition of OVA.

View larger version (30K): [in this window] [in a new window]   FIGURE 2. Local administration of MLNs obtained from tracheally tolerized anti-OVA TCR mice reduced both Th1- and Th2-induced cutaneous inflammation more efficiently than systemic administration. Th1 or Th2 were prepared by short-term culture of splenocytes from anti-OVA TCR mice. MLNs were obtained from anti-OVA TCR mice given OVA intratracheally 7 days before the experiment (see Materials and Methods). Increasing numbers of MLNs obtained from tolerized anti-OVA TCR mice were injected s.c. into the right ear lobe with Th1 or Th2 cells (1 x 106 cells/site). As few as 1 x 105 MLNs reduce both types of T cell-induced ear swelling. The suppressive effect on Th1- or Th2-induced ear swelling almost reached a plateau at a dose of 1 x 106 cells/site, when the ear thickness was evaluated at 48 or 24 h after the injection, respectively. Control splenocytes or MLNs from naive anti-OVA TCR mice did not have an inhibitory effect. There were statistically significant differences (*, p < 0.05; **, p < 0.01).

View larger version (39K): [in this window] [in a new window]   FIGURE 3. CD4+ cells were responsible for the suppressive effects of MLNs from tracheally tolerized mice on Th1- and Th2-mediated cutaneous inflammation. Indicated numbers of CD4+ or CD8+ cells were injected into the right ear lobe with Th1 or Th2 cells (1 x 106 cells/site) and OVA (100 µg/ml). CD4+ cells suppressed Th1- and Th2-induced ear swelling to an extent similar to that of bulk MLNs. CD8+ cells did not significantly affect ear swelling. There were statistically significant differences (**, p < 0.01).

In vivo suppressive effects of MLNs from tolerized mice were mediated by direct action of TGF- and partly through immunoregulatory effects of IL-10

We next examined whether TGF- or IL-10 mediated the inhibition of Th1- and Th2-induced cutaneous inflammation, because we previously demonstrated that MLNs cultured in the presence of OVA produced TGF- (12) and little IL-10 (our unpublished observation). Concomitant injection of MLNs from tolerized mice with Th1 or Th2 cells inhibited cutaneous inflammation (Fig. 4). Anti-TGF- mAb (0.3–3 µg/mouse) mitigated the suppressive effects of MLNs, whereas isotype control mAbs had no effect. Suppressed cutaneous inflammation fully reverted to control levels following high doses of anti-TGF- mAb in both the Th1- and Th2-dependent models (Fig. 4), suggesting that the inhibition of inflammation is primarily due to TGF- secreted from MLNs, but it does not seem to be responsible for IL-10 produced by themselves.

View larger version (36K): [in this window] [in a new window]   FIGURE 4. The suppressive effects of MLNs from tolerized mice on Th-mediated inflammation were mediated by direct action of TGF- and partly through the immunoregulatory effects of IL-10. Th1 or Th2 cells were prepared by short-term culture of splenocytes from anti-OVA TCR mice. MLNs were obtained from anti-OVA TCR mice given OVA intratracheally 7 days before the experiment (see Materials and Methods). MLNs (1 x 106 cells/site) obtained from tolerized anti-OVA TCR mice were injected s.c. into the right ear lobe with Th1 or Th2 cells (1 x 106 cells/site) and OVA (100 µg/ml) in the presence or absence of neutralizing Abs, anti-TGF-, or anti-IL-10 mAb. The addition of anti-TGF- or anti-IL-10 mAb to the injection mixture significantly affected the inhibitory effects of the MLNs on Th1- and Th2-mediated ear swelling. Lower concentrations (0.3 or 1 µg/ml) of anti-IL-10 mAb were less effective than the corresponding amount of anti-TGF- mAb. Anti-IL-10 mAb less effectively mediated the suppressive action of MLNs on Th2-induced inflammation than on Th1-induced inflammation. None of the isotype control Abs affected the inhibition.

These results prompted us to further clarify the relationship between TGF- and IL-10 using rTGF- instead of MLNs from tolerized mice in this Th-induced cutaneous inflammation model. rTGF- inhibited Th1- and Th2-induced cutaneous inflammation in a dose-dependent manner (Fig. 5a). The inhibition by TGF- was specific, because other cytokines, including IL-3, IL-4, IL-18, and TNF-, were not inhibitory on Th-mediated cutaneous inflammation (Fig. 5b). The inhibition of Th1-mediated cutaneous inflammation by rTGF- was totally reversed by neutralization of IL-10 (Fig. 6). In contrast, Th2-mediated inflammation was only partially reversed by anti-IL-10 mAb, further substantiating the differential susceptibility of Th1- and Th2-mediated inflammation to TGF- and IL-10 as observed with suppressive MLNs (Fig. 6).

View larger version (20K): [in this window] [in a new window]   FIGURE 5. The addition of rTGF- reduced Th-induced ear swelling. a, The addition of rTGF- resulted in a dose-dependent reduction of Th-induced ear swelling. b, The ear swelling was not affected by other cytokines, including IL-3, IL-4, IL-18, and TNF-, indicating that the suppressive effects of rTGF- were specific. Th1 or Th2 cells were prepared by short-term culture of splenocytes from anti-OVA TCR mice. Th1 or Th2 cells (1 x 106 cells/site) and OVA (100 µg/ml) were injected into their right ear lobes in the presence of increasing doses of rTGF-. There were statistically significant differences (**, p < 0.01).

View larger version (32K): [in this window] [in a new window]   FIGURE 6. The inhibitory effect of rTGF- on Th-mediated ear swelling was decreased by anti-IL-10 mAb. Th1 or Th2 cells were prepared by short-term culture of splenocytes from anti-OVA TCR mice. Th1 or Th2 cells (1 x 106 cells/site) and OVA (100 µg/ml) were injected into the right ear lobes in the presence of rTGF- with or without anti-IL-10 mAb. There were statistically significant differences (**, p < 0.01).

View larger version (30K): [in this window] [in a new window]   FIGURE 7. The addition of rIL-10 reduced Th-induced ear swelling. Th1 or Th2 cells were prepared by short-term culture of splenocytes from anti-OVA TCR mice. Th1 or Th2 cells (1 x 106 cells/site) and OVA (100 µg/ml) were injected into their right ear lobes in the presence of increasing doses of rIL-10. There were statistically significant differences (*, p < 0.05; **, p < 0.01). ND, No difference.

View larger version (28K): [in this window] [in a new window]   FIGURE 8. The inhibitory effect of rIL-10 on Th-mediated ear swelling was not affected by anti-TGF- mAb. Th1 or Th2 cells were prepared by short-term culture of splenocytes from anti-OVA TCR mice. Th1 or Th2 cells (1 x 106 cells/site) and OVA (100 µg/ml) were injected into the right ear lobes in the presence of rIL-10 with or without anti-TGF- mAb. There were statistically significant differences (**, p < 0.01).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The results of the present study demonstrate that ear swelling induced by s.c. injection of Th1 or Th2 cells in naive mice was suppressed by MLNs obtained from mice tracheally tolerized to OVA. We previously demonstrated that MLNs cultured in the presence of OVA produced TGF- (12) and little IL-10 (our unpublished observation), thus these cytokines were presumed to be involved in the suppression of ear swelling. Suppression was indeed induced by the concomitant injection of rTGF- or rIL-10. However, using neutralizing Abs Th1- and Th2-induced inflammation was differentially sensitive to TGF- and IL-10. The inhibitory effects of MLNs were blocked by anti-TGF- mAb in both Th1- and Th2-induced inflammation, suggesting irrelevance of IL-10 produced by MLNs themselves to the inhibition. The MLN- or rTGF--induced inhibition was partially reversed by anti-IL-10 mAb in Th2-induced inflammation, whereas the inhibition was significantly reversed in Th1-induced inflammation. We also demonstrated that higher doses of rIL-10 were required to obtain the substantial suppression of Th2-induced skin inflammation to the same extent as that found in Th1-induced one, although rIL-10 suppressed each Th-induced ear swelling in a dose-dependent fashion. These results indicate that cutaneous inflammation induced by Th1 cells is more refractory to TGF- and more susceptible to IL-10 induced by TGF- than the inflammation induced by Th2 cells.

Although we could not identify the cell source of IL-10 production, there are several lines of evidence suggesting that TGF- enhances IL-10 production by APC such as monocyte/macrophages (26, 27, 28), and that murine epidermal keratinocytes produce IL-10 (25). The TGF- produced by MLNs may thus have both a direct suppressive effect on Th1- and Th2-mediated ear swelling and an indirect effect via the action of IL-10 produced by local monocytes/macrophages or epidermal keratinocytes. Furthermore, because preliminary FACS analyses disclosed that Th1 and Th2 cells did not express detectable levels of a IL-10R on their cell surfaces, targets of IL-10 seem to be other cells than Th cells such as eosinophils.

The mechanisms underlying oral tolerance have been studied extensively. The induction of suppressor cells producing TGF- can produce high-dose oral tolerance in anti-OVA TCR tg mice (29, 30). Our colleagues recently reported that mice tolerized by oral administration of a high dose of OVA suppressed eosinophil-mediated inflammation in the trachea, and that TGF- produced by splenocytes from the tolerant mice was responsible for the suppression of the bronchial Th2-mediated inflammation (12).

In addition to the oral tolerance described by Marth et al. (29) and Chen et al. (30), many investigators have recently focused on peripheral tolerance induced via the respiratory tract, namely tracheal tolerance. The cytokines involved and the phenotype of cytokine-secreting cells associated with tracheal tolerance are quite variable among different experimental conditions. For example, repeated Ag inhalation induces Ag-specific suppression of IgE production mediated by IFN--secreting CD8⁺ T cells (13, 14, 15) or by T cells (31). In contrast, Haneda et al. (20) demonstrated that intratracheal administration of high-dose Ag suppresses eosinophil-mediated inflammation in the trachea and that this tolerance is induced by TGF--producing CD4⁺ T cells. Thus, intratracheally administered Ags suppress both IgE and eosinophilic responses, which are orchestrated by Th2 cells (32).

There are also several reports indicating that tracheal or intranasal Ag administration can suppress Th1-mediated immune responses in disorders such as uveoretinitis, experimental autoimmune encephalomyelitis, arthritis, and diabetes (16, 17, 18, 19, 33, 34). The cytokine involved in these processes either remains to be determined (16, 17, 33, 34) or is secreted from Th2 cells, which then inhibit Th1-mediated experimental autoimmune diseases (18, 19). In the present experiment we found that TGF--producing suppressor cells from tracheally tolerized mice controlled both Th1- and Th2-mediated cutaneous inflammation. This is a novel effect that has not been studied before in tracheal tolerance models.

The suppressive effects demonstrated in the present experiments were mediated by two well-known anti-inflammatory cytokines, TGF- and IL-10. Their inhibitory functions have been explained by several mechanisms. TGF- has strong immunoregulatory effects through its inhibitory action on the growth of T cells, B cells, NK cells, and thymocytes, and their functions (35, 36). These suppressive effects are partly explained by the inhibitory influence of TGF- on the Ag presentation function of Langerhans cells (37) and on the production of IFN- and IFN- (36). The importance of TGF- as a natural anti-inflammatory cytokine is highlighted by the multiorgan inflammatory changes in TGF- knockout mice (38, 39). IL-10 also down-regulates Th1 cell activation by altering Ag presentation of Langerhans cells via suppression of B7-1, although it does not significantly affect B7-2 expression by Langerhans cells (40). IL-10 knockout mice develop Th1-mediated inflammatory bowel disease-like colitis; the administration of IL-10 to these mice results in regression of the colitis (41). Additionally, colitis induced by CD4⁺CD45RB^high splenic T cells is abolished by the induction of T regulatory cells producing both IL-10 and TGF- with IL-4 (42).

Patients with AD represent a heterogeneous group of individuals. Despite having a similar phenotype or distribution of cutaneous symptoms and eruptions, they have varying allergic backgrounds (43). Some AD and/or asthma patients experience allergic responses to airborne protein Ags that subsequently regress spontaneously with age (44). Airborne proteins may gain access to the body more easily through the bronchial mucous membranes than through the stratum corneum of the skin, because the stratum corneum does not allow salient penetration of substances with a molecular mass larger than 500 Da. In fact, there is substantial evidence indicating that inhalation of an airborne allergen, the house dust mite, induces exacerbation of pre-existing skin exanthemas and/or new induction of erythemata (45). We dermatologists have underestimated the roles of the respiratory tract for the onset or maintenance of AD and for the induction of tracheal tolerance associated with allergy against airborne Ags. The results obtained using the present tracheal tolerance model at least partially explain how inhaled airborne allergens can induce the hyporesponsiveness of Th1- and Th2-mediated cutaneous immune reactions in these patients. The findings of the present study might be useful in the future development of novel therapeutic strategies for the induction of Ag-specific peripheral tolerance.

	Footnotes

 
¹ This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Address correspondence and reprint requests to Dr. Tadashi Terui, Department of Dermatology, Tohoku University School of Medicine, Seiryo-machi 1-1, Aoba-ku, Sendai 980-8574, Japan. E-mail address: terui{at}mail.cc.tohoku.ac.jp

³ Abbreviations used in this paper: AD, atopic dermatitis; tg, transgenic; MLN, mediastinal lymph node.

Received for publication March 28, 2001. Accepted for publication July 19, 2001.

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