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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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Primary in vivo  CTL response against influenza  virus in WT mice (a), and mice  with a targeted mutation of HSA  (b), CD28 (c), or of both HSA  and CD28 (d). Spleen cells were  harvested from mice on day 7 after A/JAP-infection. The CTL  activities were tested on either  peptide (AA365-380 of the nucleoprotein from A/JAP virus)- pulsed (EL4-NP), or unpulsed  EL4 cells (EL4). Representatives  of three independent experiments using pooled spleen cells  from 2–4 mice in each group are  shown.
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Figure 3: Primary in vivo CTL response against influenza virus in WT mice (a), and mice with a targeted mutation of HSA (b), CD28 (c), or of both HSA and CD28 (d). Spleen cells were harvested from mice on day 7 after A/JAP-infection. The CTL activities were tested on either peptide (AA365-380 of the nucleoprotein from A/JAP virus)- pulsed (EL4-NP), or unpulsed EL4 cells (EL4). Representatives of three independent experiments using pooled spleen cells from 2–4 mice in each group are shown.

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)

Primary in vivo  CTL response against influenza  virus in WT mice (a), and mice  with a targeted mutation of HSA  (b), CD28 (c), or of both HSA  and CD28 (d). Spleen cells were  harvested from mice on day 7 after A/JAP-infection. The CTL  activities were tested on either  peptide (AA365-380 of the nucleoprotein from A/JAP virus)- pulsed (EL4-NP), or unpulsed  EL4 cells (EL4). Representatives  of three independent experiments using pooled spleen cells  from 2–4 mice in each group are  shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196124&req=5

Figure 3: Primary in vivo CTL response against influenza virus in WT mice (a), and mice with a targeted mutation of HSA (b), CD28 (c), or of both HSA and CD28 (d). Spleen cells were harvested from mice on day 7 after A/JAP-infection. The CTL activities were tested on either peptide (AA365-380 of the nucleoprotein from A/JAP virus)- pulsed (EL4-NP), or unpulsed EL4 cells (EL4). Representatives of three independent experiments using pooled spleen cells from 2–4 mice in each group are shown.
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