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Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T lymphocytes.

Liu Y, Wenger RH, Zhao M, Nielsen PJ - J. Exp. Med. (1997)

Bottom Line: Furthermore, our results revealed that B7 is essential for the generation of effector T cells from either naive or memory T cells, while HSA is not necessary for the generation of effector T cells.Our results demonstrate that the induction of memory T cells and effector T cells can utilize distinct costimulatory molecules.These results have important implications on lineage relationship between effector and memory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University Medical Center, New York 10016, USA.

ABSTRACT
A successful T cell immune response has two major products: effector T cells which directly or indirectly remove the antigens, and memory T cells, which allow a faster and more efficient recall response when challenged by related antigens. An important issue is whether costimulatory molecules on the antigen-presenting cells are involved in determining whether T cells will differentiate into effector or memory cells after antigenic stimulation. To address this issue, we have produced mice with targeted mutations of either the heat-stable antigen (HSA), or both HSA and CD28. We show that CD28/B7 and HSA provide two alternative costimulatory pathways for induction of immunological memory to influenza virus. Furthermore, our results revealed that B7 is essential for the generation of effector T cells from either naive or memory T cells, while HSA is not necessary for the generation of effector T cells. Our results demonstrate that the induction of memory T cells and effector T cells can utilize distinct costimulatory molecules. These results have important implications on lineage relationship between effector and memory T cells.

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Either HSA or CD28-mediated costimulation is sufficient for  generation of primed T cells: bulk cultures. (a and b) Anti-HSA mAb  20C9 blocks T cell memory in CD28KO (b) but not WT mice (a), as  measured by recall CTL responses in vitro. CD28-deficient mice and syngeneic WT mice were treated with either normal hamster Ig or anti-HSA  mAb (300 μg/mouse/injection) on day −1, day 0, and day 1. On day 0,  these mice were injected intraperitoneally with influenza virus A/JAP  (1,000 HAU/mouse), spleen cells were harvested on day 7; and were restimulated with A/JAP-infected (1,000 HAU/12 × 106 cells, 37°C,1 h),  irradiated syngeneic spleen cells for 5 d (responder: stimulator ratio 5:1,  with responder cells at a density of 106/ml). At the end of culturing, viable cells were harvested and the cytotoxicity of these cells was determined  by a 6 h 51Cr-release assay. (c) Recall CTL responses in mice with different targeted mutations. The pooled spleen cells from groups of 2–3 mice  were harvested on day 7 after i.v. injection of A/JAP (300 HAU), recall  CTL activity determined as in a and b. Representatives of 2–3 independent experiments are shown. Note overall CTL responses in c are stronger than in a and b due to a stronger priming via i.v. injection. Dashed  lines are the lysis of EL-4 cells in the absence of NP peptide.
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Figure 6: Either HSA or CD28-mediated costimulation is sufficient for generation of primed T cells: bulk cultures. (a and b) Anti-HSA mAb 20C9 blocks T cell memory in CD28KO (b) but not WT mice (a), as measured by recall CTL responses in vitro. CD28-deficient mice and syngeneic WT mice were treated with either normal hamster Ig or anti-HSA mAb (300 μg/mouse/injection) on day −1, day 0, and day 1. On day 0, these mice were injected intraperitoneally with influenza virus A/JAP (1,000 HAU/mouse), spleen cells were harvested on day 7; and were restimulated with A/JAP-infected (1,000 HAU/12 × 106 cells, 37°C,1 h), irradiated syngeneic spleen cells for 5 d (responder: stimulator ratio 5:1, with responder cells at a density of 106/ml). At the end of culturing, viable cells were harvested and the cytotoxicity of these cells was determined by a 6 h 51Cr-release assay. (c) Recall CTL responses in mice with different targeted mutations. The pooled spleen cells from groups of 2–3 mice were harvested on day 7 after i.v. injection of A/JAP (300 HAU), recall CTL activity determined as in a and b. Representatives of 2–3 independent experiments are shown. Note overall CTL responses in c are stronger than in a and b due to a stronger priming via i.v. injection. Dashed lines are the lysis of EL-4 cells in the absence of NP peptide.

Mentions: Several recent studies demonstrated that T cells can be primed in mice with a targeted mutation of CD28 (CD28KO) (39), or transgenic for CTLA4-Ig (which very effectively blocks the interaction of B7-1 and B7-2 with CD28 and CTLA4) (40). To test whether costimulation by HSA accounts for this priming, we injected anti-HSA mAb into CD28KO mice. As shown in Fig. 6, the recall CTL response generated in CD28KO mice was inhibited almost completely by pre-treatment with anti-HSA during priming. In contrast, the priming to influenza virus in WT mice was not significantly affected by anti-HSA mAb. These results demonstrate that the targeted mutation of CD28 renders the CTL priming more dependent on costimulation by HSA.


Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T lymphocytes.

Liu Y, Wenger RH, Zhao M, Nielsen PJ - J. Exp. Med. (1997)

Either HSA or CD28-mediated costimulation is sufficient for  generation of primed T cells: bulk cultures. (a and b) Anti-HSA mAb  20C9 blocks T cell memory in CD28KO (b) but not WT mice (a), as  measured by recall CTL responses in vitro. CD28-deficient mice and syngeneic WT mice were treated with either normal hamster Ig or anti-HSA  mAb (300 μg/mouse/injection) on day −1, day 0, and day 1. On day 0,  these mice were injected intraperitoneally with influenza virus A/JAP  (1,000 HAU/mouse), spleen cells were harvested on day 7; and were restimulated with A/JAP-infected (1,000 HAU/12 × 106 cells, 37°C,1 h),  irradiated syngeneic spleen cells for 5 d (responder: stimulator ratio 5:1,  with responder cells at a density of 106/ml). At the end of culturing, viable cells were harvested and the cytotoxicity of these cells was determined  by a 6 h 51Cr-release assay. (c) Recall CTL responses in mice with different targeted mutations. The pooled spleen cells from groups of 2–3 mice  were harvested on day 7 after i.v. injection of A/JAP (300 HAU), recall  CTL activity determined as in a and b. Representatives of 2–3 independent experiments are shown. Note overall CTL responses in c are stronger than in a and b due to a stronger priming via i.v. injection. Dashed  lines are the lysis of EL-4 cells in the absence of NP peptide.
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Related In: Results  -  Collection

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Figure 6: Either HSA or CD28-mediated costimulation is sufficient for generation of primed T cells: bulk cultures. (a and b) Anti-HSA mAb 20C9 blocks T cell memory in CD28KO (b) but not WT mice (a), as measured by recall CTL responses in vitro. CD28-deficient mice and syngeneic WT mice were treated with either normal hamster Ig or anti-HSA mAb (300 μg/mouse/injection) on day −1, day 0, and day 1. On day 0, these mice were injected intraperitoneally with influenza virus A/JAP (1,000 HAU/mouse), spleen cells were harvested on day 7; and were restimulated with A/JAP-infected (1,000 HAU/12 × 106 cells, 37°C,1 h), irradiated syngeneic spleen cells for 5 d (responder: stimulator ratio 5:1, with responder cells at a density of 106/ml). At the end of culturing, viable cells were harvested and the cytotoxicity of these cells was determined by a 6 h 51Cr-release assay. (c) Recall CTL responses in mice with different targeted mutations. The pooled spleen cells from groups of 2–3 mice were harvested on day 7 after i.v. injection of A/JAP (300 HAU), recall CTL activity determined as in a and b. Representatives of 2–3 independent experiments are shown. Note overall CTL responses in c are stronger than in a and b due to a stronger priming via i.v. injection. Dashed lines are the lysis of EL-4 cells in the absence of NP peptide.
Mentions: Several recent studies demonstrated that T cells can be primed in mice with a targeted mutation of CD28 (CD28KO) (39), or transgenic for CTLA4-Ig (which very effectively blocks the interaction of B7-1 and B7-2 with CD28 and CTLA4) (40). To test whether costimulation by HSA accounts for this priming, we injected anti-HSA mAb into CD28KO mice. As shown in Fig. 6, the recall CTL response generated in CD28KO mice was inhibited almost completely by pre-treatment with anti-HSA during priming. In contrast, the priming to influenza virus in WT mice was not significantly affected by anti-HSA mAb. These results demonstrate that the targeted mutation of CD28 renders the CTL priming more dependent on costimulation by HSA.

Bottom Line: Furthermore, our results revealed that B7 is essential for the generation of effector T cells from either naive or memory T cells, while HSA is not necessary for the generation of effector T cells.Our results demonstrate that the induction of memory T cells and effector T cells can utilize distinct costimulatory molecules.These results have important implications on lineage relationship between effector and memory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University Medical Center, New York 10016, USA.

ABSTRACT
A successful T cell immune response has two major products: effector T cells which directly or indirectly remove the antigens, and memory T cells, which allow a faster and more efficient recall response when challenged by related antigens. An important issue is whether costimulatory molecules on the antigen-presenting cells are involved in determining whether T cells will differentiate into effector or memory cells after antigenic stimulation. To address this issue, we have produced mice with targeted mutations of either the heat-stable antigen (HSA), or both HSA and CD28. We show that CD28/B7 and HSA provide two alternative costimulatory pathways for induction of immunological memory to influenza virus. Furthermore, our results revealed that B7 is essential for the generation of effector T cells from either naive or memory T cells, while HSA is not necessary for the generation of effector T cells. Our results demonstrate that the induction of memory T cells and effector T cells can utilize distinct costimulatory molecules. These results have important implications on lineage relationship between effector and memory T cells.

Show MeSH
Related in: MedlinePlus