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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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Anti-B7 mAbs  completely block the production of effector CTL from naive  T cells in both WT mice (a) or  HSA-KO (b) mice. WT and mutant mice were infected with  1,000 HAU/mouse of influenza  virus A/JAP by intraperitoneal  injection on day 0. The mice  were injected with either a mixture of normal rat and hamster  IgG, or anti-B7-1 + anti-B7-2  mAbs (3A12+GL1) on days −1,  0, +1, at a dose of 100 μg/ mouse/injection. Data presented  are representative of three experiments using pooled spleen cells  from 2–3 mice per group.
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Figure 4: Anti-B7 mAbs completely block the production of effector CTL from naive T cells in both WT mice (a) or HSA-KO (b) mice. WT and mutant mice were infected with 1,000 HAU/mouse of influenza virus A/JAP by intraperitoneal injection on day 0. The mice were injected with either a mixture of normal rat and hamster IgG, or anti-B7-1 + anti-B7-2 mAbs (3A12+GL1) on days −1, 0, +1, at a dose of 100 μg/ mouse/injection. Data presented are representative of three experiments using pooled spleen cells from 2–3 mice per group.

Mentions: As shown in Fig. 3, WT and HSA-deficient mice mount a significant primary CTL response against NP-peptidepulsed syngeneic EL4 target cells, but not against unpulsed EL-4, (Fig. 3, a and b), or peptide-pulsed allogeneic P815 (H-2d) targets (data not shown). The kinetics of the CTL response is similar in all mice (data not shown). Although in this experiment, the primary CTL response in HSA- deficient mice is somewhat lower than WT mice, in other experiments, HSA-KO mice appear to mount a higher primary CTL response (data not shown). Thus HSA is not required for the generation of primary CTL. In contrast, no virus-specific primary CTL response is detected in mice deficient for either CD28, or both CD28 and HSA, although in some experiments, a significant nonspecific cytotoxicity was detected in CD28-deficient mice, most likely due to NK cells. This lack of CTL response was not due to a change in the kinetics, since we have been unable to detect primary responses against influenza virus between day 3 and day 14, in mice with a targeted mutation of CD28 (data not shown). Because CD28 is the major receptor for the costimulatory molecules B7-1/2, these results strongly suggest that B7 is necessary for the induction of primary CTL. This is more directly demonstrated by the results in Fig. 4, which show that a mixture of anti-B7-1/B7-2 completely eliminates the primary anti-influenza NP CTL response in both WT and HSA-deficient mice. In contrast, anti-HSA mAb 20C9 does not block primary effector CTL responses (data not shown). These results also demonstrate that anti-B7 mAbs efficiently block the function of B7 in vivo.


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)

Anti-B7 mAbs  completely block the production of effector CTL from naive  T cells in both WT mice (a) or  HSA-KO (b) mice. WT and mutant mice were infected with  1,000 HAU/mouse of influenza  virus A/JAP by intraperitoneal  injection on day 0. The mice  were injected with either a mixture of normal rat and hamster  IgG, or anti-B7-1 + anti-B7-2  mAbs (3A12+GL1) on days −1,  0, +1, at a dose of 100 μg/ mouse/injection. Data presented  are representative of three experiments using pooled spleen cells  from 2–3 mice per group.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196124&req=5

Figure 4: Anti-B7 mAbs completely block the production of effector CTL from naive T cells in both WT mice (a) or HSA-KO (b) mice. WT and mutant mice were infected with 1,000 HAU/mouse of influenza virus A/JAP by intraperitoneal injection on day 0. The mice were injected with either a mixture of normal rat and hamster IgG, or anti-B7-1 + anti-B7-2 mAbs (3A12+GL1) on days −1, 0, +1, at a dose of 100 μg/ mouse/injection. Data presented are representative of three experiments using pooled spleen cells from 2–3 mice per group.
Mentions: As shown in Fig. 3, WT and HSA-deficient mice mount a significant primary CTL response against NP-peptidepulsed syngeneic EL4 target cells, but not against unpulsed EL-4, (Fig. 3, a and b), or peptide-pulsed allogeneic P815 (H-2d) targets (data not shown). The kinetics of the CTL response is similar in all mice (data not shown). Although in this experiment, the primary CTL response in HSA- deficient mice is somewhat lower than WT mice, in other experiments, HSA-KO mice appear to mount a higher primary CTL response (data not shown). Thus HSA is not required for the generation of primary CTL. In contrast, no virus-specific primary CTL response is detected in mice deficient for either CD28, or both CD28 and HSA, although in some experiments, a significant nonspecific cytotoxicity was detected in CD28-deficient mice, most likely due to NK cells. This lack of CTL response was not due to a change in the kinetics, since we have been unable to detect primary responses against influenza virus between day 3 and day 14, in mice with a targeted mutation of CD28 (data not shown). Because CD28 is the major receptor for the costimulatory molecules B7-1/2, these results strongly suggest that B7 is necessary for the induction of primary CTL. This is more directly demonstrated by the results in Fig. 4, which show that a mixture of anti-B7-1/B7-2 completely eliminates the primary anti-influenza NP CTL response in both WT and HSA-deficient mice. In contrast, anti-HSA mAb 20C9 does not block primary effector CTL responses (data not shown). These results also demonstrate that anti-B7 mAbs efficiently block the function of B7 in vivo.

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