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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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Split responses of  the F5 transgenic T cells to peptides corresponding to AA366– 374 of nucleoprotein from influenza virus A/PR8/34 (H1N1),  A/Ann Arbor/60 (H2N2), and  A/NT/68 (H3N2). (a) Proliferative T cell response. F5 spleen  cells (2 × 105/well) were stimulated with given concentration of  the viral peptides or control P1A  peptides for 48 h. Proliferation of  T cells was determined by incorporation of [3H]TdR pulsed during the last 6 h of culture. (b) Specificity of activated F5 CTLs. F5 spleen cells (5 × 105/ml) were stimulated with 0.1 μg/ml of the H3N2 NP peptide  for 4 d. Viable cells were isolated and used as effector cells. EL4 cells were labeled using 51Cr and added to 96-well plates containing varying concentrations of peptides. Effector/target ratio is 60:1 for all groups.
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Figure 1: Split responses of the F5 transgenic T cells to peptides corresponding to AA366– 374 of nucleoprotein from influenza virus A/PR8/34 (H1N1), A/Ann Arbor/60 (H2N2), and A/NT/68 (H3N2). (a) Proliferative T cell response. F5 spleen cells (2 × 105/well) were stimulated with given concentration of the viral peptides or control P1A peptides for 48 h. Proliferation of T cells was determined by incorporation of [3H]TdR pulsed during the last 6 h of culture. (b) Specificity of activated F5 CTLs. F5 spleen cells (5 × 105/ml) were stimulated with 0.1 μg/ml of the H3N2 NP peptide for 4 d. Viable cells were isolated and used as effector cells. EL4 cells were labeled using 51Cr and added to 96-well plates containing varying concentrations of peptides. Effector/target ratio is 60:1 for all groups.

Mentions: The α and β chains for TCR in the F5 transgenic mice were cloned from a CTL clone, F5, which kills target cells pulsed with peptide from a H3N2 virus (NP366–374) but not those pulsed with the homologous peptide from a H1N1 virus (17). To test whether naive transgenic T cells have the same specificity, we isolated spleen cells from the F5 mice and tested their proliferative responses to the NP366–374 peptides from H1N1, H2N2, and H3N2 virus. The NP peptides from H3N2 and H1N1 viruses each differ from H2N2 NP peptide in one amino acid, at either position 7 or 8. As shown in Fig. 1 a, the H1N1 NP peptide induces significant proliferative responses of the transgenic T cells. However, 100-fold more H1N1 peptide than H3N2 peptide is needed to achieve similar levels of proliferation. Interestingly, H2N2 NP peptides are ∼100-fold more efficient than the peptide from H3N2 virus that induced the F5 T cells in the first place. The proliferation is specific, as control peptide from a tumor antigen P1A, which binds H-2Ld but not Db, induces no proliferative responses at all doses tested.


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)

Split responses of  the F5 transgenic T cells to peptides corresponding to AA366– 374 of nucleoprotein from influenza virus A/PR8/34 (H1N1),  A/Ann Arbor/60 (H2N2), and  A/NT/68 (H3N2). (a) Proliferative T cell response. F5 spleen  cells (2 × 105/well) were stimulated with given concentration of  the viral peptides or control P1A  peptides for 48 h. Proliferation of  T cells was determined by incorporation of [3H]TdR pulsed during the last 6 h of culture. (b) Specificity of activated F5 CTLs. F5 spleen cells (5 × 105/ml) were stimulated with 0.1 μg/ml of the H3N2 NP peptide  for 4 d. Viable cells were isolated and used as effector cells. EL4 cells were labeled using 51Cr and added to 96-well plates containing varying concentrations of peptides. Effector/target ratio is 60:1 for all groups.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Split responses of the F5 transgenic T cells to peptides corresponding to AA366– 374 of nucleoprotein from influenza virus A/PR8/34 (H1N1), A/Ann Arbor/60 (H2N2), and A/NT/68 (H3N2). (a) Proliferative T cell response. F5 spleen cells (2 × 105/well) were stimulated with given concentration of the viral peptides or control P1A peptides for 48 h. Proliferation of T cells was determined by incorporation of [3H]TdR pulsed during the last 6 h of culture. (b) Specificity of activated F5 CTLs. F5 spleen cells (5 × 105/ml) were stimulated with 0.1 μg/ml of the H3N2 NP peptide for 4 d. Viable cells were isolated and used as effector cells. EL4 cells were labeled using 51Cr and added to 96-well plates containing varying concentrations of peptides. Effector/target ratio is 60:1 for all groups.
Mentions: The α and β chains for TCR in the F5 transgenic mice were cloned from a CTL clone, F5, which kills target cells pulsed with peptide from a H3N2 virus (NP366–374) but not those pulsed with the homologous peptide from a H1N1 virus (17). To test whether naive transgenic T cells have the same specificity, we isolated spleen cells from the F5 mice and tested their proliferative responses to the NP366–374 peptides from H1N1, H2N2, and H3N2 virus. The NP peptides from H3N2 and H1N1 viruses each differ from H2N2 NP peptide in one amino acid, at either position 7 or 8. As shown in Fig. 1 a, the H1N1 NP peptide induces significant proliferative responses of the transgenic T cells. However, 100-fold more H1N1 peptide than H3N2 peptide is needed to achieve similar levels of proliferation. Interestingly, H2N2 NP peptides are ∼100-fold more efficient than the peptide from H3N2 virus that induced the F5 T cells in the first place. The proliferation is specific, as control peptide from a tumor antigen P1A, which binds H-2Ld but not Db, induces no proliferative responses at all doses tested.

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