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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 reduced tumorigenicity of the J558 cells in immune competent mice and induced protection to subsequent challenge with the parental tumors. (A) Tumor incidence of J558-Neo (n = 6) and J558-B7H (n = 10) in immune competent mice. Data are representative of four independent experiments. In total, 24/26 mice receiving J558-Neo cells developed tumors, while 23/39 mice receiving the J558-B7H cells developed tumors. (B) J558-B7H and J558-Neo tumors grew at a similar rate in syngeneic RAG-2−/− mice (n = 7). Data shown are representative of four independent experiments, which in total involved 23 mice per group. All mice developed tumors within 2 wk. Syngeneic BALB/c or BALB/crag2−/− mice received 5 × 106 tumor cells in the flank, and the tumor incidences were determined by physical examination. (C and D) Mice that rejected J558-B7H tumors were immune to subsequent challenge with parental J558 cells. Syngeneic BALB/c mice that had rejected J558-B7H tumors and naive control mice were challenged with 5 × 106 J558 cells at the opposite flank. The tumor incidence (C) and growth kinetics (D) were measured by physical examination. This experiment was repeated twice with similar results.
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fig2: B7H expression reduced tumorigenicity of the J558 cells in immune competent mice and induced protection to subsequent challenge with the parental tumors. (A) Tumor incidence of J558-Neo (n = 6) and J558-B7H (n = 10) in immune competent mice. Data are representative of four independent experiments. In total, 24/26 mice receiving J558-Neo cells developed tumors, while 23/39 mice receiving the J558-B7H cells developed tumors. (B) J558-B7H and J558-Neo tumors grew at a similar rate in syngeneic RAG-2−/− mice (n = 7). Data shown are representative of four independent experiments, which in total involved 23 mice per group. All mice developed tumors within 2 wk. Syngeneic BALB/c or BALB/crag2−/− mice received 5 × 106 tumor cells in the flank, and the tumor incidences were determined by physical examination. (C and D) Mice that rejected J558-B7H tumors were immune to subsequent challenge with parental J558 cells. Syngeneic BALB/c mice that had rejected J558-B7H tumors and naive control mice were challenged with 5 × 106 J558 cells at the opposite flank. The tumor incidence (C) and growth kinetics (D) were measured by physical examination. This experiment was repeated twice with similar results.

Mentions: Expression of GFP as a cytosolic protein drastically reduced the growth rate of the J558 cells in vitro and the tumorigencity of J558 even in RAG-2−/− mice that do not have T and B lymphocytes (data not shown). This is not the case for B7H-GFP, which was expressed on the cell surface and did not affect cell growth rate and tumorigenicity in the absence of T and B lymphocytes (Fig. 2 B; see also Figs. 7 B and 8 C). We therefore used J558 cells transfected with vector alone as control for this study. We tested the tumorigenicity of the J558-B7H and J558-Neo in syngeneic BALB/c mice. As shown in Fig. 2, all mice that received the J558-Neo tumor cells developed palpable tumors within 11 d, while only 10% of the mice inoculated with the J558-B7H cells developed tumors during the same period. Although 60% of the mice did develop tumors within a 6-wk period, the remaining 40% of the mice never developed tumors. In contrast, in the immune deficient RAG-2−/− mice, the two tumor cell lines induced tumors at a similar rate. Thus, while nonspecific immunity may cause a minor reduction of the tumorigenicity of the B7H-transfected J558 cells, the decreased tumorigenicity of the B7H-transfected tumor cells is primarily due to specific immune response. To confirm that the immunity was not solely specific for any part of the B7H-GFP fusion protein, we challenged the mice that had rejected the J558-B7H tumor with the parental J558 cells. As shown in Fig. 2, C and D, while 100% of the naive mice developed the J558 tumors at the site of injection, none of the mice that rejected the J558-B7H tumors develop the J558 tumors.


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 reduced tumorigenicity of the J558 cells in immune competent mice and induced protection to subsequent challenge with the parental tumors. (A) Tumor incidence of J558-Neo (n = 6) and J558-B7H (n = 10) in immune competent mice. Data are representative of four independent experiments. In total, 24/26 mice receiving J558-Neo cells developed tumors, while 23/39 mice receiving the J558-B7H cells developed tumors. (B) J558-B7H and J558-Neo tumors grew at a similar rate in syngeneic RAG-2−/− mice (n = 7). Data shown are representative of four independent experiments, which in total involved 23 mice per group. All mice developed tumors within 2 wk. Syngeneic BALB/c or BALB/crag2−/− mice received 5 × 106 tumor cells in the flank, and the tumor incidences were determined by physical examination. (C and D) Mice that rejected J558-B7H tumors were immune to subsequent challenge with parental J558 cells. Syngeneic BALB/c mice that had rejected J558-B7H tumors and naive control mice were challenged with 5 × 106 J558 cells at the opposite flank. The tumor incidence (C) and growth kinetics (D) were measured by physical examination. This experiment was repeated twice with similar results.
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Related In: Results  -  Collection

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

fig2: B7H expression reduced tumorigenicity of the J558 cells in immune competent mice and induced protection to subsequent challenge with the parental tumors. (A) Tumor incidence of J558-Neo (n = 6) and J558-B7H (n = 10) in immune competent mice. Data are representative of four independent experiments. In total, 24/26 mice receiving J558-Neo cells developed tumors, while 23/39 mice receiving the J558-B7H cells developed tumors. (B) J558-B7H and J558-Neo tumors grew at a similar rate in syngeneic RAG-2−/− mice (n = 7). Data shown are representative of four independent experiments, which in total involved 23 mice per group. All mice developed tumors within 2 wk. Syngeneic BALB/c or BALB/crag2−/− mice received 5 × 106 tumor cells in the flank, and the tumor incidences were determined by physical examination. (C and D) Mice that rejected J558-B7H tumors were immune to subsequent challenge with parental J558 cells. Syngeneic BALB/c mice that had rejected J558-B7H tumors and naive control mice were challenged with 5 × 106 J558 cells at the opposite flank. The tumor incidence (C) and growth kinetics (D) were measured by physical examination. This experiment was repeated twice with similar results.
Mentions: Expression of GFP as a cytosolic protein drastically reduced the growth rate of the J558 cells in vitro and the tumorigencity of J558 even in RAG-2−/− mice that do not have T and B lymphocytes (data not shown). This is not the case for B7H-GFP, which was expressed on the cell surface and did not affect cell growth rate and tumorigenicity in the absence of T and B lymphocytes (Fig. 2 B; see also Figs. 7 B and 8 C). We therefore used J558 cells transfected with vector alone as control for this study. We tested the tumorigenicity of the J558-B7H and J558-Neo in syngeneic BALB/c mice. As shown in Fig. 2, all mice that received the J558-Neo tumor cells developed palpable tumors within 11 d, while only 10% of the mice inoculated with the J558-B7H cells developed tumors during the same period. Although 60% of the mice did develop tumors within a 6-wk period, the remaining 40% of the mice never developed tumors. In contrast, in the immune deficient RAG-2−/− mice, the two tumor cell lines induced tumors at a similar rate. Thus, while nonspecific immunity may cause a minor reduction of the tumorigenicity of the B7H-transfected J558 cells, the decreased tumorigenicity of the B7H-transfected tumor cells is primarily due to specific immune response. To confirm that the immunity was not solely specific for any part of the B7H-GFP fusion protein, we challenged the mice that had rejected the J558-B7H tumor with the parental J558 cells. As shown in Fig. 2, C and D, while 100% of the naive mice developed the J558 tumors at the site of injection, none of the mice that rejected the J558-B7H tumors develop the J558 tumors.

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