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Comparative Study
. 2006 Dec 19;103(51):19454-9.
doi: 10.1073/pnas.0609706104. Epub 2006 Dec 11.

CD27 mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector differentiation

James M Carr  1 , Marlene J Carrasco, James E D Thaventhiran, Paul J Bambrough, Matthew Kraman, Alexander D Edwards, Aymen Al-Shamkhani, Douglas T Fearon
Affiliations
Comparative Study

CD27 mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector differentiation

James M Carr et al. Proc Natl Acad Sci U S A. .

Abstract

The clonal expansion of antigen-specific CD8+ T cells in response to microbial infections is essential for adaptive immunity. Although IL-2 has been considered to be primarily responsible for this process, quantitatively normal expansion occurs in the absence of IL-2 receptor signaling. Here, we show that ligating CD27 on CD8+ T cells that have been stimulated through the T cell receptor causes their expansion in the absence of IL-2 by mediating two distinct cellular processes: enhancing cell cycling and promoting cell survival by maintaining the expression of IL-7 receptor alpha. This pathway for clonal expansion of the CD8+ T cell is not associated with the development of a capacity either for production of IFN-gamma or for cytotoxic T lymphocyte function and, therefore, is uncoupled from differentiation. Furthermore, ligating CD27 increases the threshold concentration at which IL-2 induces IFN-gamma-producing capability by the CD8+ T cell, suggesting that CD27 signaling may suppress effector differentiation. Finally, CD8+ T cells that have been stimulated by the TCR/CD27 pathway maintain their capacity for subsequent expansion and effector differentiation in response to a viral challenge in vivo. Thus, the TCR/CD27 pathway enables the CD8+ T cell to replicate by a process of self-renewal, which may contribute to the continuous generation of new effector CD8+ T cells in persistent viral infections.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The TNF receptor superfamily members, CD27 and CD137, and CD8+ T cell expansion in the presence of blocking antibodies to IL-2 and CD25. OT-I CD8+ T cells were stimulated with mitomycin C-treated A20 cells in the presence or absence of 20 ng/ml anti-CD3ε, IL-7, and anti-IL-2/anti-CD25. Cultures contained the indicated blocking or isotype control antibodies. After 45 h, CD8+ T cells were restimulated by using the original culture conditions and then assessed for expansion at 90 h. Comparable results were obtained in three similar experiments.
Fig. 2.
Fig. 2.
TCR/CD27-mediated clonal expansion and maintenance of IL-7Rα expression. CFSE-labeled OT-I CD8+ T cells were stimulated in the presence or absence of IL-7 with A20 cells, anti-CD3ε plus anti-IL-2/anti-CD25, and the indicated antibodies. At 90 h, CD8+ T cells were assessed for expansion (a), CFSE profiles (b), and IL-7Rα expression (c). (b) Dotted histograms represent unstimulated cells. (c) Solid and dotted histograms represent staining with a specific antibody and isotype control, respectively. Comparable results were obtained in three similar experiments.
Fig. 3.
Fig. 3.
TCR/CD27-mediated clonal expansion in an IL-2−/− CD8+ T cell-only system. IL-2−/− OT-I CD8+ T cells were cultured with variable concentrations of OVA peptide and either 2.5 nM sCD70 or anti-CD70. After 40 h, cells were restimulated with the original conditions plus IL-7 and then assessed at 82 h for expansion (a) and CFSE profiles (b) of unstimulated (dotted histogram) and stimulated (solid histogram) cells. Comparable results were obtained in three similar experiments.
Fig. 4.
Fig. 4.
TCR/CD27 mediated clonal expansion without effector differentiation. (a) IL-2−/− OT-I CD8+ T cells were cultured with 1 nM OVA peptide and anti-CD70 or variable concentrations of sCD70. After 45 h, cells were restimulated with the original conditions, with or without IL-7, and then assessed for expansion at 90 h. (b) IL-2−/− CD8+ T cells were stimulated with 1 nM OVA peptide and 2.5 nM sCD70 or with 1 nM OVA peptide and IL-2 in the presence of anti-CD70. After 45 h, cells with sCD70 were restimulated with the original conditions plus IL-7, whereas cells with IL-2 were restimulated only by the addition of IL-2 and IL-7. Naïve and 90-h cultured CD8+ T cells were assessed for expression of selected proteins and capacity for cytokine synthesis after restimulation with OVA peptide (intracellular cytokine stain) (solid histogram, specific antibody; dotted histogram, isotype control). Numbers in histograms represent the mean fluorescence intensity of staining with specific antibody. Comparable results were obtained in three similar experiments.
Fig. 5.
Fig. 5.
CD27 costimulation and suppression of IL-2-mediated effector differentiation of CD8+ T cells. IL-2−/− OT-I CD8+ T cells were stimulated with 1 nM OVA peptide and increasing concentrations of IL-2 in the presence of either 1.5 nM sCD70-Ig (a and c) or anti-CD70 (b and d). After 45 h, cells were restimulated with the original conditions plus IL-7 and then assessed at 90 h for expansion (a and b) and expression of granzyme B and capacity for IFN-γ synthesis after restimulation with OVA peptide (c and d). (c and d Left) Solid and dotted histograms represent staining with specific antibody and isotype control, respectively. (c and d Right) Solid and dotted histograms represent specific IFN-γ staining in cells restimulated or not with peptide, respectively. Numbers in histograms represent the mean fluorescence intensity of staining for granzyme B and for IFN-γ in peptide-stimulated cells. Comparable results were obtained in two similar experiments.
Fig. 6.
Fig. 6.
TCR/CD27-stimulated CD8+ T cells in vitro as progenitors of virally induced effector cells in vivo. Thy1.2+ OT-I CD8+ T cells were stimulated with 1 nM OVA peptide and 0.9 nM sCD70-Ig in the presence of anti-IL-2/anti-CD25. After 45 and 90 h, cells were restimulated by using the original culture conditions plus IL-7. After 5 days, the CD8+ T cells were assessed for expression of granzyme B and CD62L and for peptide-induced IFN-γ synthesis, and 10,000 of these cells were adoptively transferred to Thy1.1+ C57BL/6 recipients. The following day, mice were infected with vaccinia-OVA. Eight days after infection, Thy1.2+, CD8+ splenocytes were reassessed for differentiation (solid histogram, specific antibody; dotted histogram, isotype control). Numbers in histograms represent the mean fluorescence intensity of staining with specific antibody. Comparable results were obtained in two similar experiments.
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