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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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Requirement of costimulatory molecules for the  generation of primed T cells assayed at 8 d after priming: microplate culture in the absence of exogenous cytokines. (a) Anti-viral  CTL of in vitro-stimulated spleen  cells from either naive or A/JAPprimed mice. (b) Requirement of  B7 family members for the generation of primed T cells. WT and  HSA-KO mice were infected with  1,000 HAU/mouse of influenza  virus A/JAP by intraperitoneal injection on day 0. On days −1, 0,  +1, these mice were injected with  either a mixture of normal rat and  hamster IgG, or anti-B7-1 + antiB7-2 mAbs (3A12+GL1) at a dose  of 100 μg/mouse/injection. Spleen  cells were harvested 8 d after viral  infection and were restimulated with  irradiated, A/JAP-infected syngeneic spleen cells for 6 d in vitro,  and CTL activity determined. Responder cells used were from pools  of two spleens. Data in b were lysis  of NP peptide (AA365-380)-pulsed  EL4 target (104/well) only. The  lysis of unpulsed EL4 cells is not  shown but was always less than  10%. Representative of three experiments, with two mice per  group are shown.
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Figure 5: Requirement of costimulatory molecules for the generation of primed T cells assayed at 8 d after priming: microplate culture in the absence of exogenous cytokines. (a) Anti-viral CTL of in vitro-stimulated spleen cells from either naive or A/JAPprimed mice. (b) Requirement of B7 family members for the generation of primed T cells. WT and HSA-KO mice were infected with 1,000 HAU/mouse of influenza virus A/JAP by intraperitoneal injection on day 0. On days −1, 0, +1, these mice were injected with either a mixture of normal rat and hamster IgG, or anti-B7-1 + antiB7-2 mAbs (3A12+GL1) at a dose of 100 μg/mouse/injection. Spleen cells were harvested 8 d after viral infection and were restimulated with irradiated, A/JAP-infected syngeneic spleen cells for 6 d in vitro, and CTL activity determined. Responder cells used were from pools of two spleens. Data in b were lysis of NP peptide (AA365-380)-pulsed EL4 target (104/well) only. The lysis of unpulsed EL4 cells is not shown but was always less than 10%. Representative of three experiments, with two mice per group are shown.

Mentions: Infection of mice with influenza virus primes a recall CTL response in vitro, detectable as early as 48 h after infection (our unpublished results). To test the requirement for costimulatory molecules in the priming of the recall CTL response, we infected WT and HSA-KO mice with influenza virus either in the presence or absence of antibodies to B7 or HSA. After 8 d, spleen cells were restimulated in vitro for 5–6 d with influenza virus-infected syngeneic spleen cells in the absence of mAbs and CTL activity was measured. Fig. 5 a shows that the recall response requires in vivo priming. In the WT mice, the recall responses were not affected by treatment with a mixture of anti-B7-1 and anti-B7-2 antibodies during priming (Fig. 5 b). In contrast, a mixture of anti-B7-1/B7-2 totally abolished the priming in the HSA-KO mice (Fig. 5 b). The efficacy of the anti-B7 mAbs in vivo is confirmed because such treatment completely eliminated primary CTL response in vivo in both WT and HSA-deficient mice (Fig. 4). Thus, costimulation by either B7 or HSA is required for the in vivo priming of the recall CTL response.


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)

Requirement of costimulatory molecules for the  generation of primed T cells assayed at 8 d after priming: microplate culture in the absence of exogenous cytokines. (a) Anti-viral  CTL of in vitro-stimulated spleen  cells from either naive or A/JAPprimed mice. (b) Requirement of  B7 family members for the generation of primed T cells. WT and  HSA-KO mice were infected with  1,000 HAU/mouse of influenza  virus A/JAP by intraperitoneal injection on day 0. On days −1, 0,  +1, these mice were injected with  either a mixture of normal rat and  hamster IgG, or anti-B7-1 + antiB7-2 mAbs (3A12+GL1) at a dose  of 100 μg/mouse/injection. Spleen  cells were harvested 8 d after viral  infection and were restimulated with  irradiated, A/JAP-infected syngeneic spleen cells for 6 d in vitro,  and CTL activity determined. Responder cells used were from pools  of two spleens. Data in b were lysis  of NP peptide (AA365-380)-pulsed  EL4 target (104/well) only. The  lysis of unpulsed EL4 cells is not  shown but was always less than  10%. Representative of three experiments, with two mice per  group are shown.
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Figure 5: Requirement of costimulatory molecules for the generation of primed T cells assayed at 8 d after priming: microplate culture in the absence of exogenous cytokines. (a) Anti-viral CTL of in vitro-stimulated spleen cells from either naive or A/JAPprimed mice. (b) Requirement of B7 family members for the generation of primed T cells. WT and HSA-KO mice were infected with 1,000 HAU/mouse of influenza virus A/JAP by intraperitoneal injection on day 0. On days −1, 0, +1, these mice were injected with either a mixture of normal rat and hamster IgG, or anti-B7-1 + antiB7-2 mAbs (3A12+GL1) at a dose of 100 μg/mouse/injection. Spleen cells were harvested 8 d after viral infection and were restimulated with irradiated, A/JAP-infected syngeneic spleen cells for 6 d in vitro, and CTL activity determined. Responder cells used were from pools of two spleens. Data in b were lysis of NP peptide (AA365-380)-pulsed EL4 target (104/well) only. The lysis of unpulsed EL4 cells is not shown but was always less than 10%. Representative of three experiments, with two mice per group are shown.
Mentions: Infection of mice with influenza virus primes a recall CTL response in vitro, detectable as early as 48 h after infection (our unpublished results). To test the requirement for costimulatory molecules in the priming of the recall CTL response, we infected WT and HSA-KO mice with influenza virus either in the presence or absence of antibodies to B7 or HSA. After 8 d, spleen cells were restimulated in vitro for 5–6 d with influenza virus-infected syngeneic spleen cells in the absence of mAbs and CTL activity was measured. Fig. 5 a shows that the recall response requires in vivo priming. In the WT mice, the recall responses were not affected by treatment with a mixture of anti-B7-1 and anti-B7-2 antibodies during priming (Fig. 5 b). In contrast, a mixture of anti-B7-1/B7-2 totally abolished the priming in the HSA-KO mice (Fig. 5 b). The efficacy of the anti-B7 mAbs in vivo is confirmed because such treatment completely eliminated primary CTL response in vivo in both WT and HSA-deficient mice (Fig. 4). Thus, costimulation by either B7 or HSA is required for the in vivo priming of the recall CTL response.

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