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Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.

Coyle AJ, Lloyd C, Tian J, Nguyen T, Erikkson C, Wang L, Ottoson P, Persson P, Delaney T, Lehar S, Lin S, Poisson L, Meisel C, Kamradt T, Bjerke T, Levinson D, Gutierrez-Ramos JC - J. Exp. Med. (1999)

Bottom Line: T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells.In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production.To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Inflammation Division, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. coyle@mpi.com

ABSTRACT
T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

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Anti-T1/ST2 mAb inhibits Th2-mediated allergic lung inflammation and airway hyperresponsiveness. Representative lung histology for Th2 recipient, OVA-exposed (a) control isotype-treated or (b) anti-T1/ST2 mAb–treated mice. Panel c shows eosinophil number in the BAL fluid (cells/ml × 104) in rat Ig–treated (black bars) or anti-T1/ST2 mAb–treated Th2 recipient mice (white bars), and data are shown as mean ± SEM of n = 5–6 animals. Similar data were generated using T1/ST2-Ig fusion protein (data not shown). Statistical significance (*P < 0.01) was determined by Student's t test. In contrast to the effects of anti-T1/ST2 mAb on Th2-mediated pathology, there was no effect of T1/ST2 mAb on Th1-mediated lung pathology (e) compared with Th1 recipient mice treated with control rat Ig (d), summarized in panel f where the circles represent individual mice treated with either rat Ig (•) or anti-T1/ST2 mAb (○). Statistical significance (*P < 0.01) was determined by Student's t test. (g) OVA exposure in control Ig–treated, Th2 recipient mice resulted in airway hyperresponsiveness (⋄) compared with recipient mice that were exposed to PBS (and treated with anti-T1/ST2 mAb; □). Pretreatment with anti-T1/ST2 mAb inhibited OVA-induced bronchial hyperresponsiveness (○). The results are shown as the mean ± SEM of n = 5–10 mice.
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Figure 5: Anti-T1/ST2 mAb inhibits Th2-mediated allergic lung inflammation and airway hyperresponsiveness. Representative lung histology for Th2 recipient, OVA-exposed (a) control isotype-treated or (b) anti-T1/ST2 mAb–treated mice. Panel c shows eosinophil number in the BAL fluid (cells/ml × 104) in rat Ig–treated (black bars) or anti-T1/ST2 mAb–treated Th2 recipient mice (white bars), and data are shown as mean ± SEM of n = 5–6 animals. Similar data were generated using T1/ST2-Ig fusion protein (data not shown). Statistical significance (*P < 0.01) was determined by Student's t test. In contrast to the effects of anti-T1/ST2 mAb on Th2-mediated pathology, there was no effect of T1/ST2 mAb on Th1-mediated lung pathology (e) compared with Th1 recipient mice treated with control rat Ig (d), summarized in panel f where the circles represent individual mice treated with either rat Ig (•) or anti-T1/ST2 mAb (○). Statistical significance (*P < 0.01) was determined by Student's t test. (g) OVA exposure in control Ig–treated, Th2 recipient mice resulted in airway hyperresponsiveness (⋄) compared with recipient mice that were exposed to PBS (and treated with anti-T1/ST2 mAb; □). Pretreatment with anti-T1/ST2 mAb inhibited OVA-induced bronchial hyperresponsiveness (○). The results are shown as the mean ± SEM of n = 5–10 mice.

Mentions: While the above data demonstrate an important role for T1/ST2 in a Th2-dominated response induced by antigen and adjuvant, it is possible that the observed effects on airway inflammation are not mediated via suppression of Th2 cells, as other cell types, including mast cells, also express T1/ST2 22. To address this issue, we next used a model of Th1 and Th2 cell adoptive transfer 23. Aeroallergen provocation of Th1 or Th2 effector cell recipient mice resulted in either a neutrophilic or eosinophilic lung mucosal inflammatory response, respectively 23. Inhibition of T1/ST2 in OVA-exposed Th2 recipient mice with either anti-T1/ST2 mAb (Fig. 4) or T1/ST2-Ig (Table ) inhibited the secretion of IL-4, IL-5, IL-6, and IL-13 in the BAL fluid by >90%. Intriguingly, IL-10 secretion was independent of T1/ST2, suggesting either that the majority of IL-10–producing cells are from a population distinct from cells that produce other Th2 cytokines or that the mechanisms of IL-10 secretion are regulated differently from other Th2 cytokines. Administration of anti-T1/ST2 mAb or T1/ST2-Ig also markedly suppressed eosinophilic inflammation of the airways as assessed both histologically (Fig. 5, a and b) and by analysis of the number of eosinophils in the BAL fluid (Fig. 5 c, and Table ). In contrast to the effects of anti-T1/ST2 mAb in Th2-mediated inflammation, inhibition of T1/ST2 did not modify Th1 effector responses as revealed either by IFN-γ secretion (Fig. 4) or Th1-mediated neutrophilic lung inflammation (Fig. 5dFig. f). Likewise, using whole body plethysmography 18, both anti-T1/ST2 mAb and T1/ST2-Ig treatment suppressed the development of airway hyperresponsiveness induced by OVA challenge in Th2 recipient mice (Fig. 5 g, and Table ) or in the active immunization model (data not shown). However, whether the ability of T1/ST2 to suppress airway hyperresponsiveness is secondary to attenuated eosinophilic inflammation or is via the suppression of other key effector molecules such as IL-13 2425 remains to be determined.


Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.

Coyle AJ, Lloyd C, Tian J, Nguyen T, Erikkson C, Wang L, Ottoson P, Persson P, Delaney T, Lehar S, Lin S, Poisson L, Meisel C, Kamradt T, Bjerke T, Levinson D, Gutierrez-Ramos JC - J. Exp. Med. (1999)

Anti-T1/ST2 mAb inhibits Th2-mediated allergic lung inflammation and airway hyperresponsiveness. Representative lung histology for Th2 recipient, OVA-exposed (a) control isotype-treated or (b) anti-T1/ST2 mAb–treated mice. Panel c shows eosinophil number in the BAL fluid (cells/ml × 104) in rat Ig–treated (black bars) or anti-T1/ST2 mAb–treated Th2 recipient mice (white bars), and data are shown as mean ± SEM of n = 5–6 animals. Similar data were generated using T1/ST2-Ig fusion protein (data not shown). Statistical significance (*P < 0.01) was determined by Student's t test. In contrast to the effects of anti-T1/ST2 mAb on Th2-mediated pathology, there was no effect of T1/ST2 mAb on Th1-mediated lung pathology (e) compared with Th1 recipient mice treated with control rat Ig (d), summarized in panel f where the circles represent individual mice treated with either rat Ig (•) or anti-T1/ST2 mAb (○). Statistical significance (*P < 0.01) was determined by Student's t test. (g) OVA exposure in control Ig–treated, Th2 recipient mice resulted in airway hyperresponsiveness (⋄) compared with recipient mice that were exposed to PBS (and treated with anti-T1/ST2 mAb; □). Pretreatment with anti-T1/ST2 mAb inhibited OVA-induced bronchial hyperresponsiveness (○). The results are shown as the mean ± SEM of n = 5–10 mice.
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Figure 5: Anti-T1/ST2 mAb inhibits Th2-mediated allergic lung inflammation and airway hyperresponsiveness. Representative lung histology for Th2 recipient, OVA-exposed (a) control isotype-treated or (b) anti-T1/ST2 mAb–treated mice. Panel c shows eosinophil number in the BAL fluid (cells/ml × 104) in rat Ig–treated (black bars) or anti-T1/ST2 mAb–treated Th2 recipient mice (white bars), and data are shown as mean ± SEM of n = 5–6 animals. Similar data were generated using T1/ST2-Ig fusion protein (data not shown). Statistical significance (*P < 0.01) was determined by Student's t test. In contrast to the effects of anti-T1/ST2 mAb on Th2-mediated pathology, there was no effect of T1/ST2 mAb on Th1-mediated lung pathology (e) compared with Th1 recipient mice treated with control rat Ig (d), summarized in panel f where the circles represent individual mice treated with either rat Ig (•) or anti-T1/ST2 mAb (○). Statistical significance (*P < 0.01) was determined by Student's t test. (g) OVA exposure in control Ig–treated, Th2 recipient mice resulted in airway hyperresponsiveness (⋄) compared with recipient mice that were exposed to PBS (and treated with anti-T1/ST2 mAb; □). Pretreatment with anti-T1/ST2 mAb inhibited OVA-induced bronchial hyperresponsiveness (○). The results are shown as the mean ± SEM of n = 5–10 mice.
Mentions: While the above data demonstrate an important role for T1/ST2 in a Th2-dominated response induced by antigen and adjuvant, it is possible that the observed effects on airway inflammation are not mediated via suppression of Th2 cells, as other cell types, including mast cells, also express T1/ST2 22. To address this issue, we next used a model of Th1 and Th2 cell adoptive transfer 23. Aeroallergen provocation of Th1 or Th2 effector cell recipient mice resulted in either a neutrophilic or eosinophilic lung mucosal inflammatory response, respectively 23. Inhibition of T1/ST2 in OVA-exposed Th2 recipient mice with either anti-T1/ST2 mAb (Fig. 4) or T1/ST2-Ig (Table ) inhibited the secretion of IL-4, IL-5, IL-6, and IL-13 in the BAL fluid by >90%. Intriguingly, IL-10 secretion was independent of T1/ST2, suggesting either that the majority of IL-10–producing cells are from a population distinct from cells that produce other Th2 cytokines or that the mechanisms of IL-10 secretion are regulated differently from other Th2 cytokines. Administration of anti-T1/ST2 mAb or T1/ST2-Ig also markedly suppressed eosinophilic inflammation of the airways as assessed both histologically (Fig. 5, a and b) and by analysis of the number of eosinophils in the BAL fluid (Fig. 5 c, and Table ). In contrast to the effects of anti-T1/ST2 mAb in Th2-mediated inflammation, inhibition of T1/ST2 did not modify Th1 effector responses as revealed either by IFN-γ secretion (Fig. 4) or Th1-mediated neutrophilic lung inflammation (Fig. 5dFig. f). Likewise, using whole body plethysmography 18, both anti-T1/ST2 mAb and T1/ST2-Ig treatment suppressed the development of airway hyperresponsiveness induced by OVA challenge in Th2 recipient mice (Fig. 5 g, and Table ) or in the active immunization model (data not shown). However, whether the ability of T1/ST2 to suppress airway hyperresponsiveness is secondary to attenuated eosinophilic inflammation or is via the suppression of other key effector molecules such as IL-13 2425 remains to be determined.

Bottom Line: T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells.In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production.To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Inflammation Division, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. coyle@mpi.com

ABSTRACT
T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.

Show MeSH
Related in: MedlinePlus