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CD40-independent pathways of T cell help for priming of CD8(+) cytotoxic T lymphocytes.

Lu Z, Yuan L, Zhou X, Sotomayor E, Levitsky HI, Pardoll DM - J. Exp. Med. (2000)

Bottom Line: We found that CD4(+) T cells can provide potent help for DCs to activate CD8(+) T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides.Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via lymphokines.Therefore, we conclude that CD4(+) help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4(+)-CD8(+) T cell communication.

View Article: PubMed Central - PubMed

Affiliation: Johns Hopkins University School of Medicine Oncology Center, Baltimore, Maryland 21231, USA.

ABSTRACT
In many cases, induction of CD8(+) CTL responses requires CD4(+) T cell help. Recently, it has been shown that a dominant pathway of CD4(+) help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4(+) T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide-specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4(+) T helper cells, respectively. We found that CD4(+) T cells can provide potent help for DCs to activate CD8(+) T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4(+) help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via lymphokines. Therefore, we conclude that CD4(+) help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4(+)-CD8(+) T cell communication.

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Adoptively transferred antigen-specific CD4+ T cells can deliver help through the CD40-independent pathway in vivo. BALB/c wild-type or CD40−/− mice (Thy1.2+/+) were injected intravenously with 3 × 106 clonotypic HA-specific CD8+ T cells (Thy1.1+/−, cl4) with or without 2.5 × 106 HA-specific clonotypic CD4+ T cells (6.5). 24 h later, mice were infected intraperitoneally with 107 PFU of vac-HA or were left untreated. 4 d after infection, spleens were removed and cells were double-stained with PE-conjugated anti-Thy1.1 antibody and FITC-conjugated anti-CD8 antibody. The double-positive population represents expansion of transferred clonotypic CD8+ T cells. The numbers shown above each graph represent the mean ± SD of three independent determinations of percentages of Thy1.1+CD8+ cells. P < 0.01, 25 ± 1.0 vs. 13.5 ± 0.07% (wild-type); P < 0.005, 8.8 ± 0.75 vs. 4.77 ± 0.72% (CD40−/−).
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Figure 5: Adoptively transferred antigen-specific CD4+ T cells can deliver help through the CD40-independent pathway in vivo. BALB/c wild-type or CD40−/− mice (Thy1.2+/+) were injected intravenously with 3 × 106 clonotypic HA-specific CD8+ T cells (Thy1.1+/−, cl4) with or without 2.5 × 106 HA-specific clonotypic CD4+ T cells (6.5). 24 h later, mice were infected intraperitoneally with 107 PFU of vac-HA or were left untreated. 4 d after infection, spleens were removed and cells were double-stained with PE-conjugated anti-Thy1.1 antibody and FITC-conjugated anti-CD8 antibody. The double-positive population represents expansion of transferred clonotypic CD8+ T cells. The numbers shown above each graph represent the mean ± SD of three independent determinations of percentages of Thy1.1+CD8+ cells. P < 0.01, 25 ± 1.0 vs. 13.5 ± 0.07% (wild-type); P < 0.005, 8.8 ± 0.75 vs. 4.77 ± 0.72% (CD40−/−).

Mentions: Given the clear in vitro evidence of CD40-independent help for CD8+ CTLs, we determined whether this could be demonstrated in vivo. We initially examined the response of adoptively transferred Tg T cells to infection with vac-HA (Fig. 5). The clonal expansion of HA-specific TCR Tg CD8+ T cells was analyzed in the presence or absence of adoptively transferred HA-specific Tg CD4+ T cells. In wild-type BALB/c mice, the presence of Tg HA-specific CD4+ T cells significantly augmented the clonal expansion of Tg HA-specific CD8+ T cells, indicating that CD4+ help for CD8+ T cell activation was indeed operative in this system. The same adoptive transfer experiments into CD40−/− BALB/c mice demonstrated two important outcomes. First, consistent with earlier reports, expansion of HA-specific CD8+ T cells was significantly reduced in CD40−/− animals relative to wild-type 9. Nonetheless, a significant CD4-dependent enhancement of HA-specific CD8+ T cell expansion was observed in the CD40−/− mice.


CD40-independent pathways of T cell help for priming of CD8(+) cytotoxic T lymphocytes.

Lu Z, Yuan L, Zhou X, Sotomayor E, Levitsky HI, Pardoll DM - J. Exp. Med. (2000)

Adoptively transferred antigen-specific CD4+ T cells can deliver help through the CD40-independent pathway in vivo. BALB/c wild-type or CD40−/− mice (Thy1.2+/+) were injected intravenously with 3 × 106 clonotypic HA-specific CD8+ T cells (Thy1.1+/−, cl4) with or without 2.5 × 106 HA-specific clonotypic CD4+ T cells (6.5). 24 h later, mice were infected intraperitoneally with 107 PFU of vac-HA or were left untreated. 4 d after infection, spleens were removed and cells were double-stained with PE-conjugated anti-Thy1.1 antibody and FITC-conjugated anti-CD8 antibody. The double-positive population represents expansion of transferred clonotypic CD8+ T cells. The numbers shown above each graph represent the mean ± SD of three independent determinations of percentages of Thy1.1+CD8+ cells. P < 0.01, 25 ± 1.0 vs. 13.5 ± 0.07% (wild-type); P < 0.005, 8.8 ± 0.75 vs. 4.77 ± 0.72% (CD40−/−).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195823&req=5

Figure 5: Adoptively transferred antigen-specific CD4+ T cells can deliver help through the CD40-independent pathway in vivo. BALB/c wild-type or CD40−/− mice (Thy1.2+/+) were injected intravenously with 3 × 106 clonotypic HA-specific CD8+ T cells (Thy1.1+/−, cl4) with or without 2.5 × 106 HA-specific clonotypic CD4+ T cells (6.5). 24 h later, mice were infected intraperitoneally with 107 PFU of vac-HA or were left untreated. 4 d after infection, spleens were removed and cells were double-stained with PE-conjugated anti-Thy1.1 antibody and FITC-conjugated anti-CD8 antibody. The double-positive population represents expansion of transferred clonotypic CD8+ T cells. The numbers shown above each graph represent the mean ± SD of three independent determinations of percentages of Thy1.1+CD8+ cells. P < 0.01, 25 ± 1.0 vs. 13.5 ± 0.07% (wild-type); P < 0.005, 8.8 ± 0.75 vs. 4.77 ± 0.72% (CD40−/−).
Mentions: Given the clear in vitro evidence of CD40-independent help for CD8+ CTLs, we determined whether this could be demonstrated in vivo. We initially examined the response of adoptively transferred Tg T cells to infection with vac-HA (Fig. 5). The clonal expansion of HA-specific TCR Tg CD8+ T cells was analyzed in the presence or absence of adoptively transferred HA-specific Tg CD4+ T cells. In wild-type BALB/c mice, the presence of Tg HA-specific CD4+ T cells significantly augmented the clonal expansion of Tg HA-specific CD8+ T cells, indicating that CD4+ help for CD8+ T cell activation was indeed operative in this system. The same adoptive transfer experiments into CD40−/− BALB/c mice demonstrated two important outcomes. First, consistent with earlier reports, expansion of HA-specific CD8+ T cells was significantly reduced in CD40−/− animals relative to wild-type 9. Nonetheless, a significant CD4-dependent enhancement of HA-specific CD8+ T cell expansion was observed in the CD40−/− mice.

Bottom Line: We found that CD4(+) T cells can provide potent help for DCs to activate CD8(+) T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides.Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via lymphokines.Therefore, we conclude that CD4(+) help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4(+)-CD8(+) T cell communication.

View Article: PubMed Central - PubMed

Affiliation: Johns Hopkins University School of Medicine Oncology Center, Baltimore, Maryland 21231, USA.

ABSTRACT
In many cases, induction of CD8(+) CTL responses requires CD4(+) T cell help. Recently, it has been shown that a dominant pathway of CD4(+) help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4(+) T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide-specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4(+) T helper cells, respectively. We found that CD4(+) T cells can provide potent help for DCs to activate CD8(+) T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4(+) help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4(+)-CD8(+) T cell communication via lymphokines. Therefore, we conclude that CD4(+) help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4(+)-CD8(+) T cell communication.

Show MeSH
Related in: MedlinePlus