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. 2010 Oct;40(10):2762-8.
doi: 10.1002/eji.200940256.

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

Ian R Humphreys  1 , Seung-Woo Lee, Morgan Jones, Andrea Loewendorf, Emma Gostick, David A Price, Chris A Benedict, Carl F Ware, Michael Croft
Affiliations
Free PMC article

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

Ian R Humphreys et al. Eur J Immunol. 2010 Oct.
Free PMC article

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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Figures

Figure 1
Figure 1
4-1BB−/− mice have elevated early but reduced persistent MCMV-specific CD8 responses. WT C57BL/6 (▪) and 4-1BB-deficient (□) mice were infected with MCMV and on days 0, 7, 14 and 30 post-infection, CD8+ cells specific for M45 (A), M57 (B), M38 (C) and m139 (D) were quantified on the basis of intracellular IFN-γ production (E and F). Numbers of peptide-specific CD8+ cells 7 (E) and 30 (F) days post-infection. Results are expressed as numbers of peptide-specific CD8+ cells/spleen and are shown as mean±SEM of four mice/group, representing three independent experiments. (G) Representative plots of M45-specific tetramer-binding CD44+ CD8+ T cells from WT (left) and 4-1BB−/− mice 7 days post-infection. Results represent eight mice from two experiments. (H) Splenic M45-specific CD8+ cell numbers 7 days after immunization with M45 peptide/CFA. Mean±SEM of four mice/group is shown. (I) Numbers of peptide specific CD4+ cells 7 days post-infection. Individual mice and mean values are shown, and data represent two independent experiments. (J) In vivo CTL assay as described in the Materials and methods section. Representative plots of loaded cells prior to transfer (top) and from MCMV-infected WT (middle) and 4-1BB−/− (bottom) mice 7 days post-infection are shown, and represent four mice/group. (K) MCMV glycoprotein B content in genomic DNA from spleens of WT and 4-1BB−/− mice 7 and 30 days post-infection was measured by qPCR and normalized to β-actin. Results are expressed as mean±SEM of three mice/group. (L) Infectious viral load in salivary glands was measured by plaque assay. Individual mice and mean values are shown. (M) Representative plots of M38- and m139-specific tetramer-binding CD8+ T cells from WT (left) and 4-1BB−/− (right) mice 30 days post-infection. Results represent 12 mice from two independent experiments. (N) Numbers of peptide specific CD4+ T cells 30 days post-infection. Individual mice are shown and data represent two independent experiments. Significance is *p<0.05, Student's t-test.
Figure 2
Figure 2
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.
Figure 3
Figure 3
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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