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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/4-1BBL interactions during acute infection promote CD8 persistence. (A) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific CD8+ cells were enumerated functionally 30 days later. (B and C) MCMV-infected WT mice were treated with IgG (▪) or α4-1BBL (□) antibody on days 0, 2 and 5 (B) or 7, 10 and 13 (C) and MCMV-specific CD8+ cells were enumerated functionally after 30 (B) or 28 (C) days. All results shown are mean numbers±SEM of four to six mice/group and representative of two independent experiments. *p<0.05, Student's t-test.
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fig03: 4-1BB/4-1BBL interactions during acute infection promote CD8 persistence. (A) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific CD8+ cells were enumerated functionally 30 days later. (B and C) MCMV-infected WT mice were treated with IgG (▪) or α4-1BBL (□) antibody on days 0, 2 and 5 (B) or 7, 10 and 13 (C) and MCMV-specific CD8+ cells were enumerated functionally after 30 (B) or 28 (C) days. All results shown are mean numbers±SEM of four to six mice/group and representative of two independent experiments. *p<0.05, Student's t-test.

Mentions: Given that 4-1BBL promotes the generation of some anti-viral memory CD8+ T-cell populations in mice, and 4-1BBL binding to 4-1BB induces the expansion of human HCMV-specific CD8+ memory T cells in vitro 30, we investigated whether 4-1BBL might control the later accumulation of inflationary CD8+ T cells. Thirty days after infection, 4-1BBL−/− mice displayed reduced accumulation of these persistent CD8+ T-cell populations (Fig. 3A), similar to the defect seen in 4-1BB−/− mice (Fig. 1F). Furthermore, we found that treatment of WT mice with a blocking α4-1BBL antibody given on days 0–5 (Fig. 3B), but not days 7–13 (Fig. 3C), post-infection, also reduced the MCMV-specific CD8+ T-cell responses measured at 1 month, suggesting that the requirement for and activity of 4-1BBL likely occurred just before or at the peak of the effector T-cell response in the first week of infection, correlating with the expression data above. As seen in 4-1BB−/− mice, impaired T-cell inflation following early 4-1BBL blockade was not associated with reduced MCMV genome load in the spleen (data not shown). Some variability in T-cell responses was seen between experimental groups, such that statistical significance was not always achieved. However, combining the 4-1BBL knockout and 4-1BBL-blocking studies together essentially replicated the defective accumulation of both M38 and m139-reactive CD8+ T cells that were seen in the absence of 4-1BB. Thus, acute MCMV-specific CD8+ T-cell responses are negatively regulated by 4-1BB, but independent of 4-1BBL, whereas late CD8+ T-cell responses are positively regulated by 4-1BB and dependent on 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/4-1BBL interactions during acute infection promote CD8 persistence. (A) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific CD8+ cells were enumerated functionally 30 days later. (B and C) MCMV-infected WT mice were treated with IgG (▪) or α4-1BBL (□) antibody on days 0, 2 and 5 (B) or 7, 10 and 13 (C) and MCMV-specific CD8+ cells were enumerated functionally after 30 (B) or 28 (C) days. All results shown are mean numbers±SEM of four to six mice/group and representative of two independent experiments. *p<0.05, Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig03: 4-1BB/4-1BBL interactions during acute infection promote CD8 persistence. (A) WT (▪) and 4-1BBL−/− (□) mice were infected with MCMV and numbers of virus-specific CD8+ cells were enumerated functionally 30 days later. (B and C) MCMV-infected WT mice were treated with IgG (▪) or α4-1BBL (□) antibody on days 0, 2 and 5 (B) or 7, 10 and 13 (C) and MCMV-specific CD8+ cells were enumerated functionally after 30 (B) or 28 (C) days. All results shown are mean numbers±SEM of four to six mice/group and representative of two independent experiments. *p<0.05, Student's t-test.
Mentions: Given that 4-1BBL promotes the generation of some anti-viral memory CD8+ T-cell populations in mice, and 4-1BBL binding to 4-1BB induces the expansion of human HCMV-specific CD8+ memory T cells in vitro 30, we investigated whether 4-1BBL might control the later accumulation of inflationary CD8+ T cells. Thirty days after infection, 4-1BBL−/− mice displayed reduced accumulation of these persistent CD8+ T-cell populations (Fig. 3A), similar to the defect seen in 4-1BB−/− mice (Fig. 1F). Furthermore, we found that treatment of WT mice with a blocking α4-1BBL antibody given on days 0–5 (Fig. 3B), but not days 7–13 (Fig. 3C), post-infection, also reduced the MCMV-specific CD8+ T-cell responses measured at 1 month, suggesting that the requirement for and activity of 4-1BBL likely occurred just before or at the peak of the effector T-cell response in the first week of infection, correlating with the expression data above. As seen in 4-1BB−/− mice, impaired T-cell inflation following early 4-1BBL blockade was not associated with reduced MCMV genome load in the spleen (data not shown). Some variability in T-cell responses was seen between experimental groups, such that statistical significance was not always achieved. However, combining the 4-1BBL knockout and 4-1BBL-blocking studies together essentially replicated the defective accumulation of both M38 and m139-reactive CD8+ T cells that were seen in the absence of 4-1BB. Thus, acute MCMV-specific CD8+ T-cell responses are negatively regulated by 4-1BB, but independent of 4-1BBL, whereas late CD8+ T-cell responses are positively regulated by 4-1BB and dependent on 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