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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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RAG-2−/− P1CTL proliferate more rapidly in mice bearing J558-B7H tumors than in the J588-Neo tumor-bearing mice, and preferentially reject B7H+ tumors. (A) Tumor rejection. RAG-2−/− BALB/c mice were inoculated with a mixture (1:1) of J558-Neo and J558-B7H cells. One group of mice also received 5 × 106 RAG-2−/− P1CTL. Tumor incidence was determined by physical examination. (B) T cell division in vivo. RAG-2−/− P1CTL were labeled with CFSE and adoptively transferred into mice that bore J558-B7H (dotted line) or J558-Neo (bold line) tumors of comparable sizes. Spleen cells were harvested at 60 h after adoptive transfer, and stained with PE-anti-Vα8 and Cy-anti-CD8 mAbs. Data shown are the histograms of CFSE intensity of the gated CD8+Vα8+ T cells (14.8% of spleen cells in the J558-B7H group and 2.2% in the J558-Neo group). (C) Preferential rejection of the B7H+ tumors. Tumors cells were isolated from mice that received 1:1 ratio of J558-B7H and J558-Neo cells with or without RAG-2−/− P1CTL. The presence of B7H+ tumor cells was measured based on the GFP+ cells. Top panels depict two representative tumors from mice that did not receive T cells, while the two bottom panels depict those that received T cells. The percentage of GFP+ cells are indicated in the panels.
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fig8: RAG-2−/− P1CTL proliferate more rapidly in mice bearing J558-B7H tumors than in the J588-Neo tumor-bearing mice, and preferentially reject B7H+ tumors. (A) Tumor rejection. RAG-2−/− BALB/c mice were inoculated with a mixture (1:1) of J558-Neo and J558-B7H cells. One group of mice also received 5 × 106 RAG-2−/− P1CTL. Tumor incidence was determined by physical examination. (B) T cell division in vivo. RAG-2−/− P1CTL were labeled with CFSE and adoptively transferred into mice that bore J558-B7H (dotted line) or J558-Neo (bold line) tumors of comparable sizes. Spleen cells were harvested at 60 h after adoptive transfer, and stained with PE-anti-Vα8 and Cy-anti-CD8 mAbs. Data shown are the histograms of CFSE intensity of the gated CD8+Vα8+ T cells (14.8% of spleen cells in the J558-B7H group and 2.2% in the J558-Neo group). (C) Preferential rejection of the B7H+ tumors. Tumors cells were isolated from mice that received 1:1 ratio of J558-B7H and J558-Neo cells with or without RAG-2−/− P1CTL. The presence of B7H+ tumor cells was measured based on the GFP+ cells. Top panels depict two representative tumors from mice that did not receive T cells, while the two bottom panels depict those that received T cells. The percentage of GFP+ cells are indicated in the panels.

Mentions: A major caveat of the above experiment is that T cells that mediate the rejection can be specific for the GFP fusion protein, as the T cells used in the above experiments were from transgenic mice that may have had rearrangement of the endogenous TCR. To rule out this possibility, we bred the P1CTL into the syngeneic RAG-2−/− background to produce the RAG-2−/− P1CTL. As shown in Fig. 8 , RAG-2−/− P1CTL was at least as efficient as the RAG+/+ P1CTL (Fig. 7) in rejecting a mixture of the J558-B7H and J558-Neo tumors. In addition, the RAG-2−/− P1CTL divided faster in mice that bore the J558-B7H tumor (Fig. 8 B), much as the RAG-+/+ P1CTL (Fig. 5). Moreover, the tumor cells that survived the RAG-2−/− P1CTL were predominantly B7H− (Fig. 8 C). These results confirmed that the function of B7H described here was not due to the antigenicity of the GFP.


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)

RAG-2−/− P1CTL proliferate more rapidly in mice bearing J558-B7H tumors than in the J588-Neo tumor-bearing mice, and preferentially reject B7H+ tumors. (A) Tumor rejection. RAG-2−/− BALB/c mice were inoculated with a mixture (1:1) of J558-Neo and J558-B7H cells. One group of mice also received 5 × 106 RAG-2−/− P1CTL. Tumor incidence was determined by physical examination. (B) T cell division in vivo. RAG-2−/− P1CTL were labeled with CFSE and adoptively transferred into mice that bore J558-B7H (dotted line) or J558-Neo (bold line) tumors of comparable sizes. Spleen cells were harvested at 60 h after adoptive transfer, and stained with PE-anti-Vα8 and Cy-anti-CD8 mAbs. Data shown are the histograms of CFSE intensity of the gated CD8+Vα8+ T cells (14.8% of spleen cells in the J558-B7H group and 2.2% in the J558-Neo group). (C) Preferential rejection of the B7H+ tumors. Tumors cells were isolated from mice that received 1:1 ratio of J558-B7H and J558-Neo cells with or without RAG-2−/− P1CTL. The presence of B7H+ tumor cells was measured based on the GFP+ cells. Top panels depict two representative tumors from mice that did not receive T cells, while the two bottom panels depict those that received T cells. The percentage of GFP+ cells are indicated in the panels.
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Related In: Results  -  Collection

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fig8: RAG-2−/− P1CTL proliferate more rapidly in mice bearing J558-B7H tumors than in the J588-Neo tumor-bearing mice, and preferentially reject B7H+ tumors. (A) Tumor rejection. RAG-2−/− BALB/c mice were inoculated with a mixture (1:1) of J558-Neo and J558-B7H cells. One group of mice also received 5 × 106 RAG-2−/− P1CTL. Tumor incidence was determined by physical examination. (B) T cell division in vivo. RAG-2−/− P1CTL were labeled with CFSE and adoptively transferred into mice that bore J558-B7H (dotted line) or J558-Neo (bold line) tumors of comparable sizes. Spleen cells were harvested at 60 h after adoptive transfer, and stained with PE-anti-Vα8 and Cy-anti-CD8 mAbs. Data shown are the histograms of CFSE intensity of the gated CD8+Vα8+ T cells (14.8% of spleen cells in the J558-B7H group and 2.2% in the J558-Neo group). (C) Preferential rejection of the B7H+ tumors. Tumors cells were isolated from mice that received 1:1 ratio of J558-B7H and J558-Neo cells with or without RAG-2−/− P1CTL. The presence of B7H+ tumor cells was measured based on the GFP+ cells. Top panels depict two representative tumors from mice that did not receive T cells, while the two bottom panels depict those that received T cells. The percentage of GFP+ cells are indicated in the panels.
Mentions: A major caveat of the above experiment is that T cells that mediate the rejection can be specific for the GFP fusion protein, as the T cells used in the above experiments were from transgenic mice that may have had rearrangement of the endogenous TCR. To rule out this possibility, we bred the P1CTL into the syngeneic RAG-2−/− background to produce the RAG-2−/− P1CTL. As shown in Fig. 8 , RAG-2−/− P1CTL was at least as efficient as the RAG+/+ P1CTL (Fig. 7) in rejecting a mixture of the J558-B7H and J558-Neo tumors. In addition, the RAG-2−/− P1CTL divided faster in mice that bore the J558-B7H tumor (Fig. 8 B), much as the RAG-+/+ P1CTL (Fig. 5). Moreover, the tumor cells that survived the RAG-2−/− P1CTL were predominantly B7H− (Fig. 8 C). These results confirmed that the function of B7H described here was not due to the antigenicity of the GFP.

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