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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 increases P1A-specific CTL in the TIL from wild-type BALB/c mice. The TIL were enriched by depletion tumor cells as described (reference 12). The cytotoxicity of the freshly isolated TIL were determined using either P1A-pulsed or unpulsed P388D1, or the J558-Neo and J558-B7H cells as targets. (A) Substantial increase of activated CD8 T cells among the TIL. The TIL were stained with PE-conjugated anti-CD8 and Cy-conjugated anti-CD44 mAbs and analyzed by flow cytometry. (B) P1A-specific CTL in the TIL from the J558-B7H, but not the J558-Neo tumors. Freshly isolated TIL were used as effectors while the P1A-pulsed and unpulsed P388D1 were used as targets. (C) TIL from J558-B7H (right panel), but not those from J558-Neo (left panel), lysed both J558-B7H and J558-Neo tumors. As in B, except that the J558-Neo and J558-B7H were also used as targets. Data shown are representative of at least three independent experiments. TIL used in A and B were isolated at day 24 of tumor injection, while those used in C were isolated on day 20 of tumor cell injection.
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fig3: B7H increases P1A-specific CTL in the TIL from wild-type BALB/c mice. The TIL were enriched by depletion tumor cells as described (reference 12). The cytotoxicity of the freshly isolated TIL were determined using either P1A-pulsed or unpulsed P388D1, or the J558-Neo and J558-B7H cells as targets. (A) Substantial increase of activated CD8 T cells among the TIL. The TIL were stained with PE-conjugated anti-CD8 and Cy-conjugated anti-CD44 mAbs and analyzed by flow cytometry. (B) P1A-specific CTL in the TIL from the J558-B7H, but not the J558-Neo tumors. Freshly isolated TIL were used as effectors while the P1A-pulsed and unpulsed P388D1 were used as targets. (C) TIL from J558-B7H (right panel), but not those from J558-Neo (left panel), lysed both J558-B7H and J558-Neo tumors. As in B, except that the J558-Neo and J558-B7H were also used as targets. Data shown are representative of at least three independent experiments. TIL used in A and B were isolated at day 24 of tumor injection, while those used in C were isolated on day 20 of tumor cell injection.

Mentions: A major tumor antigen in the J558 tumor is P1A (30). To verify that expression of B7H on the tumor cells enhances antitumor immune response, we evaluated anti-P1A CTL response in tumor-infiltrating lymphocytes (TILs) from the J558-Neo and J558-B7H tumors. As shown in Fig. 3 A, J558-B7H was infiltrated a large number of CD8+ T cells, and essentially all CD8+ T cells expressed high levels of CD44. While J558-Neo was also infiltrated with activated CD8 T cells, its frequency was ∼20-fold lower. Moreover, strong P1A-specific CTL activity was observed in the TIL of the J558-B7H tumors, but not in those of the J558-Neo tumors (Fig. 3 B). TIL from J558-B7H kills both J558-B7H and J558-Neo targets (Fig. 3 C). Thus, B7H enhanced antitumor CTL response, including the anti-P1A CTL response in vivo.


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 increases P1A-specific CTL in the TIL from wild-type BALB/c mice. The TIL were enriched by depletion tumor cells as described (reference 12). The cytotoxicity of the freshly isolated TIL were determined using either P1A-pulsed or unpulsed P388D1, or the J558-Neo and J558-B7H cells as targets. (A) Substantial increase of activated CD8 T cells among the TIL. The TIL were stained with PE-conjugated anti-CD8 and Cy-conjugated anti-CD44 mAbs and analyzed by flow cytometry. (B) P1A-specific CTL in the TIL from the J558-B7H, but not the J558-Neo tumors. Freshly isolated TIL were used as effectors while the P1A-pulsed and unpulsed P388D1 were used as targets. (C) TIL from J558-B7H (right panel), but not those from J558-Neo (left panel), lysed both J558-B7H and J558-Neo tumors. As in B, except that the J558-Neo and J558-B7H were also used as targets. Data shown are representative of at least three independent experiments. TIL used in A and B were isolated at day 24 of tumor injection, while those used in C were isolated on day 20 of tumor cell injection.
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Related In: Results  -  Collection

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fig3: B7H increases P1A-specific CTL in the TIL from wild-type BALB/c mice. The TIL were enriched by depletion tumor cells as described (reference 12). The cytotoxicity of the freshly isolated TIL were determined using either P1A-pulsed or unpulsed P388D1, or the J558-Neo and J558-B7H cells as targets. (A) Substantial increase of activated CD8 T cells among the TIL. The TIL were stained with PE-conjugated anti-CD8 and Cy-conjugated anti-CD44 mAbs and analyzed by flow cytometry. (B) P1A-specific CTL in the TIL from the J558-B7H, but not the J558-Neo tumors. Freshly isolated TIL were used as effectors while the P1A-pulsed and unpulsed P388D1 were used as targets. (C) TIL from J558-B7H (right panel), but not those from J558-Neo (left panel), lysed both J558-B7H and J558-Neo tumors. As in B, except that the J558-Neo and J558-B7H were also used as targets. Data shown are representative of at least three independent experiments. TIL used in A and B were isolated at day 24 of tumor injection, while those used in C were isolated on day 20 of tumor cell injection.
Mentions: A major tumor antigen in the J558 tumor is P1A (30). To verify that expression of B7H on the tumor cells enhances antitumor immune response, we evaluated anti-P1A CTL response in tumor-infiltrating lymphocytes (TILs) from the J558-Neo and J558-B7H tumors. As shown in Fig. 3 A, J558-B7H was infiltrated a large number of CD8+ T cells, and essentially all CD8+ T cells expressed high levels of CD44. While J558-Neo was also infiltrated with activated CD8 T cells, its frequency was ∼20-fold lower. Moreover, strong P1A-specific CTL activity was observed in the TIL of the J558-B7H tumors, but not in those of the J558-Neo tumors (Fig. 3 B). TIL from J558-B7H kills both J558-B7H and J558-Neo targets (Fig. 3 C). Thus, B7H enhanced antitumor CTL response, including the anti-P1A CTL response in vivo.

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