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Costimulation by B7 modulates specificity of cytotoxic T lymphocytes: a missing link that explains some bystander T cell activation.

Zheng P, Liu Y - J. Exp. Med. (1997)

Bottom Line: However, this hypothesis is not supported by direct evidence since no TCR ligand is known to induce T cell proliferation and differentiation without being recognized by the effector CTL.Our results revealed that this is the case.These data demonstrated that costimulatory molecule B7 modulates antigen specificity of CTLs, and provides a missing link that explains some of the bystander T cell activation.

View Article: PubMed Central - PubMed

Affiliation: Michael Heidelberger Division of Immunology, Department of Pathology, New York University Medical Center 10016, USA.

ABSTRACT
It has been proposed that some bystander T cell activation may in fact be due to T cell antigen receptor (TCR) cross-reactivity that is too low to be detected by the effector cytotoxic T lymphocyte (CTL). However, this hypothesis is not supported by direct evidence since no TCR ligand is known to induce T cell proliferation and differentiation without being recognized by the effector CTL. Here we report that transgenic T cells expressing a T cell receptor to influenza virus A/NT/68 nucleoprotein (NP) 366-374:Db complexes clonally expand and become effector CTLs in response to homologous peptides from either A/PR8/34 (H1N1), A/AA/60 (H2N2), or A/NT/68 (H3N2). However, the effector T cells induced by each of the three peptides kill target cells pulsed with NP peptides from the H3N2 and H2N2 viruses, but not from the H1N1 virus. Thus, NP366-374 from influenza virus H1N1 is the first TCR ligand that can induce T cell proliferation and differentiation without being recognized by CTLs. Since induction of T cell proliferation was mediated by antigen-presenting cells that express costimulatory molecules such as B7, we investigated if cytolysis of H1N1 NP peptide-pulsed targets can be restored by expressing B7-1 on the target cells. Our results revealed that this is the case. These data demonstrated that costimulatory molecule B7 modulates antigen specificity of CTLs, and provides a missing link that explains some of the bystander T cell activation.

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Modulation of  CTL specificity by costimulatory molecule B7-1. (a) Expression of B7-1 in EL4 cells transfected with vector alone (top) or  B7-1 cDNA (bottom). Data presented are FACS® histograms of  fluorescences in the presence  (solid lines) and absence of anti– B7-1 mAb 3A12. (b) Fine specificity of F5 CTL using EL4-Neo  or EL4-B7 targets. See Fig. 1 legends for details of the CTL assay.
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Figure 5: Modulation of CTL specificity by costimulatory molecule B7-1. (a) Expression of B7-1 in EL4 cells transfected with vector alone (top) or B7-1 cDNA (bottom). Data presented are FACS® histograms of fluorescences in the presence (solid lines) and absence of anti– B7-1 mAb 3A12. (b) Fine specificity of F5 CTL using EL4-Neo or EL4-B7 targets. See Fig. 1 legends for details of the CTL assay.

Mentions: Proliferation assays used spleen accessory cells expressing multiple costimulatory molecules. In contrast, the CTL assay used EL4 thymoma devoid of costimulatory activity as targets (20). Therefore, it is possible that the split T cell response was due to the presence or absence of costimulatory activity in the cells used to measure cross-reactivity. To test this possibility, we transfected B7-1 into the EL4 cells. As shown in Fig. 5 a, EL4 cells transfected with vector alone have no detectable B7-1, while B7-1–transfected EL4 cells express high level of B7-1. Therefore, we compared cytolysis of EL4-Neo and EL4-B7 in the presence of various viral peptides. As shown in Fig. 5 b, EL4-Neo cells are lysed in the presence of H2N2 and H3N2 NP peptides, but not in the presence of H1N1 or control P1A peptides. In contrast, EL4-B7 targets are lysed in the presence of H1N1 NP peptide. Thus, expression of B7-1 on target cells restores F5 CTL recognition of H1N1 NP peptide–pulsed target cells. To our knowledge, this is the first evidence that costimulation by B7-1 modulates CTL specificity.


Costimulation by B7 modulates specificity of cytotoxic T lymphocytes: a missing link that explains some bystander T cell activation.

Zheng P, Liu Y - J. Exp. Med. (1997)

Modulation of  CTL specificity by costimulatory molecule B7-1. (a) Expression of B7-1 in EL4 cells transfected with vector alone (top) or  B7-1 cDNA (bottom). Data presented are FACS® histograms of  fluorescences in the presence  (solid lines) and absence of anti– B7-1 mAb 3A12. (b) Fine specificity of F5 CTL using EL4-Neo  or EL4-B7 targets. See Fig. 1 legends for details of the CTL assay.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199130&req=5

Figure 5: Modulation of CTL specificity by costimulatory molecule B7-1. (a) Expression of B7-1 in EL4 cells transfected with vector alone (top) or B7-1 cDNA (bottom). Data presented are FACS® histograms of fluorescences in the presence (solid lines) and absence of anti– B7-1 mAb 3A12. (b) Fine specificity of F5 CTL using EL4-Neo or EL4-B7 targets. See Fig. 1 legends for details of the CTL assay.
Mentions: Proliferation assays used spleen accessory cells expressing multiple costimulatory molecules. In contrast, the CTL assay used EL4 thymoma devoid of costimulatory activity as targets (20). Therefore, it is possible that the split T cell response was due to the presence or absence of costimulatory activity in the cells used to measure cross-reactivity. To test this possibility, we transfected B7-1 into the EL4 cells. As shown in Fig. 5 a, EL4 cells transfected with vector alone have no detectable B7-1, while B7-1–transfected EL4 cells express high level of B7-1. Therefore, we compared cytolysis of EL4-Neo and EL4-B7 in the presence of various viral peptides. As shown in Fig. 5 b, EL4-Neo cells are lysed in the presence of H2N2 and H3N2 NP peptides, but not in the presence of H1N1 or control P1A peptides. In contrast, EL4-B7 targets are lysed in the presence of H1N1 NP peptide. Thus, expression of B7-1 on target cells restores F5 CTL recognition of H1N1 NP peptide–pulsed target cells. To our knowledge, this is the first evidence that costimulation by B7-1 modulates CTL specificity.

Bottom Line: However, this hypothesis is not supported by direct evidence since no TCR ligand is known to induce T cell proliferation and differentiation without being recognized by the effector CTL.Our results revealed that this is the case.These data demonstrated that costimulatory molecule B7 modulates antigen specificity of CTLs, and provides a missing link that explains some of the bystander T cell activation.

View Article: PubMed Central - PubMed

Affiliation: Michael Heidelberger Division of Immunology, Department of Pathology, New York University Medical Center 10016, USA.

ABSTRACT
It has been proposed that some bystander T cell activation may in fact be due to T cell antigen receptor (TCR) cross-reactivity that is too low to be detected by the effector cytotoxic T lymphocyte (CTL). However, this hypothesis is not supported by direct evidence since no TCR ligand is known to induce T cell proliferation and differentiation without being recognized by the effector CTL. Here we report that transgenic T cells expressing a T cell receptor to influenza virus A/NT/68 nucleoprotein (NP) 366-374:Db complexes clonally expand and become effector CTLs in response to homologous peptides from either A/PR8/34 (H1N1), A/AA/60 (H2N2), or A/NT/68 (H3N2). However, the effector T cells induced by each of the three peptides kill target cells pulsed with NP peptides from the H3N2 and H2N2 viruses, but not from the H1N1 virus. Thus, NP366-374 from influenza virus H1N1 is the first TCR ligand that can induce T cell proliferation and differentiation without being recognized by CTLs. Since induction of T cell proliferation was mediated by antigen-presenting cells that express costimulatory molecules such as B7, we investigated if cytolysis of H1N1 NP peptide-pulsed targets can be restored by expressing B7-1 on the target cells. Our results revealed that this is the case. These data demonstrated that costimulatory molecule B7 modulates antigen specificity of CTLs, and provides a missing link that explains some of the bystander T cell activation.

Show MeSH
Related in: MedlinePlus