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Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo.

Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, Sato T, Habu S, Tashiro H, Sato M, Ohta A - J. Exp. Med. (1999)

Bottom Line: Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8(+) cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy.Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1-dependent cell-cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy.These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.

View Article: PubMed Central - PubMed

Affiliation: Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Isehara, Japan.

ABSTRACT
The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8(+) T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell-deficient RAG2(-/-) mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8(+) cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1-dependent cell-cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.

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Th1 and Th2 cells use distinct cell adhesion interactions during eradication of tumors in vivo. (A) Expression of LFA-1 antigen on Th1 and Th2 cells. (B) Expression of ICAM-1 on Th1 and Th2 cells. Dotted line, unstained control cells. (C and D) LFA-1/ICAM-1–dependent homotypic cell–cell aggregation. Th1 (C) and Th2 cells (D) (2 × 106 cells) were stimulated with 20 ng/ml of PMA. After culture for 1 h, homotypic aggregates were formed. Typical cell–cell aggregates were photographed. We confirmed that the homotypic aggregation was strongly blocked by addition of either anti–LFA-1 mAb or anti–ICAM-1 mAb (data not shown). (E and F) The effect of anti–LFA-1 mAb administration in vivo on the therapeutic ability of Th1 (E) or Th2 cells (F) was examined using the protocol described in the legend to Fig. 2 A. (E) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th1 cell transfer (•), or Th1 cell transfer after anti–LFA-1 mAb administration (▵). (F) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th2 cell transfer (•), or Th2 cell transfer after anti–LFA-1 mAb administration (▵). The anti–LFA-1 mAb (500 μg/mouse) was intravenously injected into the mice at days −1 and 0 before cell transfer. The antitumor activity of Th1 and Th2 cells was determined by measuring changes over time of the means of two perpendicular diameters of the tumor mass. Results are presented as mean ± SE of six mice. The tumor-free mice were followed for >90 d.
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Figure 8: Th1 and Th2 cells use distinct cell adhesion interactions during eradication of tumors in vivo. (A) Expression of LFA-1 antigen on Th1 and Th2 cells. (B) Expression of ICAM-1 on Th1 and Th2 cells. Dotted line, unstained control cells. (C and D) LFA-1/ICAM-1–dependent homotypic cell–cell aggregation. Th1 (C) and Th2 cells (D) (2 × 106 cells) were stimulated with 20 ng/ml of PMA. After culture for 1 h, homotypic aggregates were formed. Typical cell–cell aggregates were photographed. We confirmed that the homotypic aggregation was strongly blocked by addition of either anti–LFA-1 mAb or anti–ICAM-1 mAb (data not shown). (E and F) The effect of anti–LFA-1 mAb administration in vivo on the therapeutic ability of Th1 (E) or Th2 cells (F) was examined using the protocol described in the legend to Fig. 2 A. (E) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th1 cell transfer (•), or Th1 cell transfer after anti–LFA-1 mAb administration (▵). (F) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th2 cell transfer (•), or Th2 cell transfer after anti–LFA-1 mAb administration (▵). The anti–LFA-1 mAb (500 μg/mouse) was intravenously injected into the mice at days −1 and 0 before cell transfer. The antitumor activity of Th1 and Th2 cells was determined by measuring changes over time of the means of two perpendicular diameters of the tumor mass. Results are presented as mean ± SE of six mice. The tumor-free mice were followed for >90 d.

Mentions: Finally, we examined the role of distinct cell adhesion molecules in Th1 and Th2 cell therapy. While investigating the expression and function of adhesion molecules involved in cell migration, we found that Th1 cells, in response to stimulation with anti-CD3 mAb and phorbol ester, show strong LFA-1/ICAM-1–dependent homotypic adhesion (28; Fig. 8 C). However, no significant cell aggregation was observed for similarly activated Th2 cells (Fig. 8 D). This homotypic cell–cell aggregation was strongly blocked by anti–LFA-1 or anti–ICAM-1 mAb, but not by control rat Ig or anti–VLA-4 mAb (data not shown). From these results, we concluded that Th1 and Th2 cells have distinct capacity to use LFA-1/ICAM-1 cell adhesion interactions. This differential ability to form homotypic cell–cell aggregates did not result from a defect in LFA-1 or ICAM-1 expression, because both Th1 and Th2 cells expressed high levels of LFA-1 and ICAM-1 at the cell surface (Fig. 5A and Fig. B). To investigate whether LFA-1/ICAM-1 interactions are important for the induction of antitumor activity in vivo, we examined the effect of anti–LFA-1 mAb administration on Th1 and Th2 cell therapy. Mice were inoculated with A20-OVA tumor cells, and when tumors became palpable, mice were treated by intravenous injection of anti–LFA-1 mAb (500 μg/mouse) twice at days −1 and 0 before adoptive transfer of Th1 or Th2 cells. As shown in Fig. 5 E, the therapeutic ability of Th1 cells was completely abrogated by anti–LFA-1 mAb administration. However, no significant inhibitory effect by anti–LFA-1 mAb was observed for Th2-mediated antitumor activity (Fig. 5 F). These results indicated that Th1 and Th2 cells showed distinct requirements for LFA-1–dependent cell–cell interactions in vitro and in vivo: LFA-1–dependent cell migration appeared to be critical for Th1-cell therapy but not for Th2-cell therapy.


Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo.

Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, Sato T, Habu S, Tashiro H, Sato M, Ohta A - J. Exp. Med. (1999)

Th1 and Th2 cells use distinct cell adhesion interactions during eradication of tumors in vivo. (A) Expression of LFA-1 antigen on Th1 and Th2 cells. (B) Expression of ICAM-1 on Th1 and Th2 cells. Dotted line, unstained control cells. (C and D) LFA-1/ICAM-1–dependent homotypic cell–cell aggregation. Th1 (C) and Th2 cells (D) (2 × 106 cells) were stimulated with 20 ng/ml of PMA. After culture for 1 h, homotypic aggregates were formed. Typical cell–cell aggregates were photographed. We confirmed that the homotypic aggregation was strongly blocked by addition of either anti–LFA-1 mAb or anti–ICAM-1 mAb (data not shown). (E and F) The effect of anti–LFA-1 mAb administration in vivo on the therapeutic ability of Th1 (E) or Th2 cells (F) was examined using the protocol described in the legend to Fig. 2 A. (E) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th1 cell transfer (•), or Th1 cell transfer after anti–LFA-1 mAb administration (▵). (F) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th2 cell transfer (•), or Th2 cell transfer after anti–LFA-1 mAb administration (▵). The anti–LFA-1 mAb (500 μg/mouse) was intravenously injected into the mice at days −1 and 0 before cell transfer. The antitumor activity of Th1 and Th2 cells was determined by measuring changes over time of the means of two perpendicular diameters of the tumor mass. Results are presented as mean ± SE of six mice. The tumor-free mice were followed for >90 d.
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Figure 8: Th1 and Th2 cells use distinct cell adhesion interactions during eradication of tumors in vivo. (A) Expression of LFA-1 antigen on Th1 and Th2 cells. (B) Expression of ICAM-1 on Th1 and Th2 cells. Dotted line, unstained control cells. (C and D) LFA-1/ICAM-1–dependent homotypic cell–cell aggregation. Th1 (C) and Th2 cells (D) (2 × 106 cells) were stimulated with 20 ng/ml of PMA. After culture for 1 h, homotypic aggregates were formed. Typical cell–cell aggregates were photographed. We confirmed that the homotypic aggregation was strongly blocked by addition of either anti–LFA-1 mAb or anti–ICAM-1 mAb (data not shown). (E and F) The effect of anti–LFA-1 mAb administration in vivo on the therapeutic ability of Th1 (E) or Th2 cells (F) was examined using the protocol described in the legend to Fig. 2 A. (E) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th1 cell transfer (•), or Th1 cell transfer after anti–LFA-1 mAb administration (▵). (F) When the A20-OVA tumor mass became palpable, the mice were treated with saline (○), Th2 cell transfer (•), or Th2 cell transfer after anti–LFA-1 mAb administration (▵). The anti–LFA-1 mAb (500 μg/mouse) was intravenously injected into the mice at days −1 and 0 before cell transfer. The antitumor activity of Th1 and Th2 cells was determined by measuring changes over time of the means of two perpendicular diameters of the tumor mass. Results are presented as mean ± SE of six mice. The tumor-free mice were followed for >90 d.
Mentions: Finally, we examined the role of distinct cell adhesion molecules in Th1 and Th2 cell therapy. While investigating the expression and function of adhesion molecules involved in cell migration, we found that Th1 cells, in response to stimulation with anti-CD3 mAb and phorbol ester, show strong LFA-1/ICAM-1–dependent homotypic adhesion (28; Fig. 8 C). However, no significant cell aggregation was observed for similarly activated Th2 cells (Fig. 8 D). This homotypic cell–cell aggregation was strongly blocked by anti–LFA-1 or anti–ICAM-1 mAb, but not by control rat Ig or anti–VLA-4 mAb (data not shown). From these results, we concluded that Th1 and Th2 cells have distinct capacity to use LFA-1/ICAM-1 cell adhesion interactions. This differential ability to form homotypic cell–cell aggregates did not result from a defect in LFA-1 or ICAM-1 expression, because both Th1 and Th2 cells expressed high levels of LFA-1 and ICAM-1 at the cell surface (Fig. 5A and Fig. B). To investigate whether LFA-1/ICAM-1 interactions are important for the induction of antitumor activity in vivo, we examined the effect of anti–LFA-1 mAb administration on Th1 and Th2 cell therapy. Mice were inoculated with A20-OVA tumor cells, and when tumors became palpable, mice were treated by intravenous injection of anti–LFA-1 mAb (500 μg/mouse) twice at days −1 and 0 before adoptive transfer of Th1 or Th2 cells. As shown in Fig. 5 E, the therapeutic ability of Th1 cells was completely abrogated by anti–LFA-1 mAb administration. However, no significant inhibitory effect by anti–LFA-1 mAb was observed for Th2-mediated antitumor activity (Fig. 5 F). These results indicated that Th1 and Th2 cells showed distinct requirements for LFA-1–dependent cell–cell interactions in vitro and in vivo: LFA-1–dependent cell migration appeared to be critical for Th1-cell therapy but not for Th2-cell therapy.

Bottom Line: Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8(+) cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy.Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1-dependent cell-cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy.These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.

View Article: PubMed Central - PubMed

Affiliation: Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Isehara, Japan.

ABSTRACT
The role of T helper type 1 (Th1) and Th2 cells in tumor immunity was investigated using Th cells induced from ovalbumin (OVA)-specific T cell receptor transgenic mice. Although Th1 cells exhibited stronger cytotoxicity than Th2 cells, both cell types completely eradicated tumors when transferred into mice bearing A20 tumor cells transfected with the OVA gene (A20-OVA). Th1 cells eradicated the tumor mass by inducing cellular immunity, whereas Th2 cells destroyed the tumor by inducing tumor necrosis. Both Th1 and Th2 cells required CD8(+) T cells to eliminate tumors, and neither of these cells were able to completely eliminate A20-OVA tumors from T and B cell-deficient RAG2(-/-) mice. Mice cured from tumors by Th1 and Th2 cell therapy rejected A20-OVA upon rechallenge, but CD8(+) cytotoxic T lymphocytes were induced only from spleen cells prepared from cured mice by Th1 cell therapy. Moreover, we demonstrated that Th1 and Th2 cells used distinct adhesion mechanisms during tumor eradication: the leukocyte function-associated antigen (LFA)-1-dependent cell-cell adhesion step was essential for Th1 cell therapy, but not for Th2 cell therapy. These findings demonstrated for the first time the distinct role of antigen-specific Th1 and Th2 cells during eradication of established tumors in vivo.

Show MeSH
Related in: MedlinePlus