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B7H costimulates clonal expansion of, and cognate destruction of tumor cells by, CD8(+) T lymphocytes in vivo.

Liu X, Bai XF, Wen J, Gao JX, Liu J, Lu P, Wang Y, Zheng P, Liu Y - J. Exp. Med. (2001)

Bottom Line: B7H/B7RP (hereby called B7H) is a new member of the B7 family of costimulatory molecules and interacts with inducible costimulatory molecule (ICOS).Its function for CD8 T cells has not been reported.Taken together, our results reveal that B7H costimulates clonal expansion of, and cognate destruction by CD8(+) T lymphocytes in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, OH 43210, USA.

ABSTRACT
B7H/B7RP (hereby called B7H) is a new member of the B7 family of costimulatory molecules and interacts with inducible costimulatory molecule (ICOS). Its function for CD8 T cells has not been reported. We report here that expression of B7H on the tumor cells reduced tumorigenicity and induced immunity to subsequent challenge with parental tumor cells. The immune protection correlates with an enhanced cytotoxic T lymphocyte (CTL) response against P1A, the major tumor antigen expressed in the J558 tumor. To understand the mechanism of immune protection, we adoptively transferred transgenic T cells specific for tumor antigen P1A into mice that bore P1A-expressing tumors. We found that while the transgenic T cells divided faster in mice bearing the B7H(+) tumors, optimal B7H-induced clonal expansion of P1CTL required costimulation by B7-1 and B7-2 on the endogenous host antigen-presenting cells (APCs). Interestingly, when B7H(+) and B7H(-) tumors were coinjected, P1CTL selectively eliminated the B7H(+) tumor cells. Moreover, B7H expressed on the tumor cells made them highly susceptible to destruction by CTL in vivo, even if the CTL was administrated into mice with large tumor burdens. Tumors that recurred in the P1CTL-treated mice lost transfected B7H and/or H-2L(d), the class I molecule that presents the P1A peptide. Taken together, our results reveal that B7H costimulates clonal expansion of, and cognate destruction by CD8(+) T lymphocytes in vivo.

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B7H expression increased susceptibility of established tumors to T cell therapy. J558-Neo and J558-B7H tumors were allowed to grow in the BALB/crag-2−/− mice for three weeks until they reached ∼1.5 cm in diameter. Transgenic T cells (5 × 106/mouse) were then injected intraperitoneally. (A) Tumor size after T cell injection. Note the complete disappearance and recurrence of the J558-B7H tumors. *, found dead; ** moribund and killed. (B). Mechanism of tumor recurrence. Analysis of cell surface expression of MHC class I H-2Ld, and B7H. Left, a J558-B7H cell line as control. Middle, phenotype of the J558-B7H-A tumor cells. Right, phenotype of the J558-B7H-B tumor cells.
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fig9: B7H expression increased susceptibility of established tumors to T cell therapy. J558-Neo and J558-B7H tumors were allowed to grow in the BALB/crag-2−/− mice for three weeks until they reached ∼1.5 cm in diameter. Transgenic T cells (5 × 106/mouse) were then injected intraperitoneally. (A) Tumor size after T cell injection. Note the complete disappearance and recurrence of the J558-B7H tumors. *, found dead; ** moribund and killed. (B). Mechanism of tumor recurrence. Analysis of cell surface expression of MHC class I H-2Ld, and B7H. Left, a J558-B7H cell line as control. Middle, phenotype of the J558-B7H-A tumor cells. Right, phenotype of the J558-B7H-B tumor cells.

Mentions: A major challenge in tumor immunotherapy is to eliminate the established tumors. As B7H promoted cognate destruction of J558 tumors, we tested if expression of B7H allowed T cells to eliminate large burdens of tumors. We injected RAG-2−/− mice with either J558-Neo or J558-B7H tumor cells. At 3 wk after tumor inoculation when the tumors had reached a diameter ∼1.5 cm, we adoptively transferred 5 × 106 P1CTL. As shown in Fig. 9 A, P1CTL caused a temporary reduction in the size of the J558-Neo tumors. However, after a short pause, the J558-Neo tumor progressed rapidly and all mice succumbed to the tumor shortly thereafter. Interestingly, in the two mice with the J558-B7H tumor and P1CTL, the tumor rapidly shrank to either impalpable (J558-B7H-A), or into a small debris of <2 mm with no tumor when examined by biopsies (J558-B7H-B). These results suggest that expression of B7H enhanced tumor susceptibility to T cell therapy.


B7H costimulates clonal expansion of, and cognate destruction of tumor cells by, CD8(+) T lymphocytes in vivo.

Liu X, Bai XF, Wen J, Gao JX, Liu J, Lu P, Wang Y, Zheng P, Liu Y - J. Exp. Med. (2001)

B7H expression increased susceptibility of established tumors to T cell therapy. J558-Neo and J558-B7H tumors were allowed to grow in the BALB/crag-2−/− mice for three weeks until they reached ∼1.5 cm in diameter. Transgenic T cells (5 × 106/mouse) were then injected intraperitoneally. (A) Tumor size after T cell injection. Note the complete disappearance and recurrence of the J558-B7H tumors. *, found dead; ** moribund and killed. (B). Mechanism of tumor recurrence. Analysis of cell surface expression of MHC class I H-2Ld, and B7H. Left, a J558-B7H cell line as control. Middle, phenotype of the J558-B7H-A tumor cells. Right, phenotype of the J558-B7H-B tumor cells.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195972&req=5

fig9: B7H expression increased susceptibility of established tumors to T cell therapy. J558-Neo and J558-B7H tumors were allowed to grow in the BALB/crag-2−/− mice for three weeks until they reached ∼1.5 cm in diameter. Transgenic T cells (5 × 106/mouse) were then injected intraperitoneally. (A) Tumor size after T cell injection. Note the complete disappearance and recurrence of the J558-B7H tumors. *, found dead; ** moribund and killed. (B). Mechanism of tumor recurrence. Analysis of cell surface expression of MHC class I H-2Ld, and B7H. Left, a J558-B7H cell line as control. Middle, phenotype of the J558-B7H-A tumor cells. Right, phenotype of the J558-B7H-B tumor cells.
Mentions: A major challenge in tumor immunotherapy is to eliminate the established tumors. As B7H promoted cognate destruction of J558 tumors, we tested if expression of B7H allowed T cells to eliminate large burdens of tumors. We injected RAG-2−/− mice with either J558-Neo or J558-B7H tumor cells. At 3 wk after tumor inoculation when the tumors had reached a diameter ∼1.5 cm, we adoptively transferred 5 × 106 P1CTL. As shown in Fig. 9 A, P1CTL caused a temporary reduction in the size of the J558-Neo tumors. However, after a short pause, the J558-Neo tumor progressed rapidly and all mice succumbed to the tumor shortly thereafter. Interestingly, in the two mice with the J558-B7H tumor and P1CTL, the tumor rapidly shrank to either impalpable (J558-B7H-A), or into a small debris of <2 mm with no tumor when examined by biopsies (J558-B7H-B). These results suggest that expression of B7H enhanced tumor susceptibility to T cell therapy.

Bottom Line: B7H/B7RP (hereby called B7H) is a new member of the B7 family of costimulatory molecules and interacts with inducible costimulatory molecule (ICOS).Its function for CD8 T cells has not been reported.Taken together, our results reveal that B7H costimulates clonal expansion of, and cognate destruction by CD8(+) T lymphocytes in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, OH 43210, USA.

ABSTRACT
B7H/B7RP (hereby called B7H) is a new member of the B7 family of costimulatory molecules and interacts with inducible costimulatory molecule (ICOS). Its function for CD8 T cells has not been reported. We report here that expression of B7H on the tumor cells reduced tumorigenicity and induced immunity to subsequent challenge with parental tumor cells. The immune protection correlates with an enhanced cytotoxic T lymphocyte (CTL) response against P1A, the major tumor antigen expressed in the J558 tumor. To understand the mechanism of immune protection, we adoptively transferred transgenic T cells specific for tumor antigen P1A into mice that bore P1A-expressing tumors. We found that while the transgenic T cells divided faster in mice bearing the B7H(+) tumors, optimal B7H-induced clonal expansion of P1CTL required costimulation by B7-1 and B7-2 on the endogenous host antigen-presenting cells (APCs). Interestingly, when B7H(+) and B7H(-) tumors were coinjected, P1CTL selectively eliminated the B7H(+) tumor cells. Moreover, B7H expressed on the tumor cells made them highly susceptible to destruction by CTL in vivo, even if the CTL was administrated into mice with large tumor burdens. Tumors that recurred in the P1CTL-treated mice lost transfected B7H and/or H-2L(d), the class I molecule that presents the P1A peptide. Taken together, our results reveal that B7H costimulates clonal expansion of, and cognate destruction by CD8(+) T lymphocytes in vivo.

Show MeSH
Related in: MedlinePlus