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Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells.

Humphreys IR, Lee SW, Jones M, Loewendorf A, Gostick E, Price DA, Benedict CA, Ware CF, Croft M - Eur. J. Immunol. (2010)

Bottom Line: CD8(+) T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations.Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8(+) T cells, whereas suppression of acute CD8(+) T cells was independent of 4-1BBL.These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. humphreysir@Cardiff.ac.uk

ABSTRACT
The initial requirement for the emergence of CMV-specific CD8(+) T cells is poorly understood. Mice deficient in the cosignaling TNF superfamily member, 4-1BB, surprisingly developed exaggerated early CD8(+) T-cell responses to mouse CMV (MCMV). CD8(+) T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations. Paradoxically, 4-1BB-deficient mice displayed reduced accumulation of memory CD8(+) T cells that expand during chronic/latent infection. Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8(+) T cells, whereas suppression of acute CD8(+) T cells was independent of 4-1BBL. These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity.

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4-1BB-mediated suppression of early anti-viral CD8+ T cells is independent of 4-1BBL. (A) WT and 4-1BB−/− mice were infected with MCMV and expression of 4-1BBL on B220+ and CD11b+CD11c+ cells was measured by flow cytometry after 3 (left panels) and 7 (right panels) days. Closed line, isotype; open line, α4-1BBL. (B) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific IFNγ+ CD8+ cells were enumerated on day 7. (C) WT mice were treated with IgG (▪) or α4-1BBL (□) on days 0, 2 and 5, and virus-specific IFNγ+ CD8+ cells were enumerated on day 7. All results shown are mean numbers±SEM of four mice/group and represent two to three independent experiments. *p<0.05, Student's t-test.
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fig02: 4-1BB-mediated suppression of early anti-viral CD8+ T cells is independent of 4-1BBL. (A) WT and 4-1BB−/− mice were infected with MCMV and expression of 4-1BBL on B220+ and CD11b+CD11c+ cells was measured by flow cytometry after 3 (left panels) and 7 (right panels) days. Closed line, isotype; open line, α4-1BBL. (B) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific IFNγ+ CD8+ cells were enumerated on day 7. (C) WT mice were treated with IgG (▪) or α4-1BBL (□) on days 0, 2 and 5, and virus-specific IFNγ+ CD8+ cells were enumerated on day 7. All results shown are mean numbers±SEM of four mice/group and represent two to three independent experiments. *p<0.05, Student's t-test.

Mentions: We next investigated whether 4-1BBL played a role in these divergent responses revealed in the absence of 4-1BB. Analyzing B6 and 4-1BB−/− mice (in which surface expression of 4-1BBL is stabilized 29), we observed that 4-1BBL was expressed by B220+ and CD11b+CD11c+ cells during acute infection, although it was more abundant at late times (day 7) rather than at early times (Fig. 2A). Analysis of 4-1BB-deficient mice at day 7, but not at day 3, showed a much higher level of 4-1BBL expression than in WT mice, implying that productive 4-1BB/4-1BBL interactions (that can result in cleavage of surface 4-1BBL) were occurring late but not early during initial infection. Correlating with this, when acute CD8+ T-cell responses were examined in 4-1BBL-deficient mice, we found no defect in the generation of any of the MCMV-reactive populations compared with WT controls (Fig. 2B). Furthermore, this result was replicated in WT mice treated with a blocking antibody to 4-1BBL given during the first week of infection (Fig. 2C). These results show that the suppressive activity of 4-1BB on acute CD8+ T-cell responses occurs independently of 4-1BBL.


Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells.

Humphreys IR, Lee SW, Jones M, Loewendorf A, Gostick E, Price DA, Benedict CA, Ware CF, Croft M - Eur. J. Immunol. (2010)

4-1BB-mediated suppression of early anti-viral CD8+ T cells is independent of 4-1BBL. (A) WT and 4-1BB−/− mice were infected with MCMV and expression of 4-1BBL on B220+ and CD11b+CD11c+ cells was measured by flow cytometry after 3 (left panels) and 7 (right panels) days. Closed line, isotype; open line, α4-1BBL. (B) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific IFNγ+ CD8+ cells were enumerated on day 7. (C) WT mice were treated with IgG (▪) or α4-1BBL (□) on days 0, 2 and 5, and virus-specific IFNγ+ CD8+ cells were enumerated on day 7. All results shown are mean numbers±SEM of four mice/group and represent two to three independent experiments. *p<0.05, Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2967573&req=5

fig02: 4-1BB-mediated suppression of early anti-viral CD8+ T cells is independent of 4-1BBL. (A) WT and 4-1BB−/− mice were infected with MCMV and expression of 4-1BBL on B220+ and CD11b+CD11c+ cells was measured by flow cytometry after 3 (left panels) and 7 (right panels) days. Closed line, isotype; open line, α4-1BBL. (B) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific IFNγ+ CD8+ cells were enumerated on day 7. (C) WT mice were treated with IgG (▪) or α4-1BBL (□) on days 0, 2 and 5, and virus-specific IFNγ+ CD8+ cells were enumerated on day 7. All results shown are mean numbers±SEM of four mice/group and represent two to three independent experiments. *p<0.05, Student's t-test.
Mentions: We next investigated whether 4-1BBL played a role in these divergent responses revealed in the absence of 4-1BB. Analyzing B6 and 4-1BB−/− mice (in which surface expression of 4-1BBL is stabilized 29), we observed that 4-1BBL was expressed by B220+ and CD11b+CD11c+ cells during acute infection, although it was more abundant at late times (day 7) rather than at early times (Fig. 2A). Analysis of 4-1BB-deficient mice at day 7, but not at day 3, showed a much higher level of 4-1BBL expression than in WT mice, implying that productive 4-1BB/4-1BBL interactions (that can result in cleavage of surface 4-1BBL) were occurring late but not early during initial infection. Correlating with this, when acute CD8+ T-cell responses were examined in 4-1BBL-deficient mice, we found no defect in the generation of any of the MCMV-reactive populations compared with WT controls (Fig. 2B). Furthermore, this result was replicated in WT mice treated with a blocking antibody to 4-1BBL given during the first week of infection (Fig. 2C). These results show that the suppressive activity of 4-1BB on acute CD8+ T-cell responses occurs independently of 4-1BBL.

Bottom Line: CD8(+) T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations.Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8(+) T cells, whereas suppression of acute CD8(+) T cells was independent of 4-1BBL.These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA. humphreysir@Cardiff.ac.uk

ABSTRACT
The initial requirement for the emergence of CMV-specific CD8(+) T cells is poorly understood. Mice deficient in the cosignaling TNF superfamily member, 4-1BB, surprisingly developed exaggerated early CD8(+) T-cell responses to mouse CMV (MCMV). CD8(+) T cells directed against acute MCMV epitopes were enhanced, demonstrating that 4-1BB naturally antagonizes these primary populations. Paradoxically, 4-1BB-deficient mice displayed reduced accumulation of memory CD8(+) T cells that expand during chronic/latent infection. Importantly, the canonical TNF-related ligand, 4-1BBL, promoted the accumulation of these memory CD8(+) T cells, whereas suppression of acute CD8(+) T cells was independent of 4-1BBL. These data highlight the dual nature of the 4-1BB/4-1BBL system in mediating both stimulatory and inhibitory cosignaling activities during the generation of anti-MCMV immunity.

Show MeSH
Related in: MedlinePlus