Late Signals from CD27 Prevent Fas-Dependent Apoptosis of Primary CD8+ T Cells

Dolfi, Douglas V.; Boesteanu, Alina C.; Petrovas, Constantinos; Xia, Dong; Butz, Eric; Katsikis, Peter D.

doi:10.4049/jimmunol.180.5.2912

Cited by 73 publications

(85 citation statements)

References 52 publications

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“…Consistent with this, during acute infection such as with influenza, when viral and antigenic loads are likely limiting, CD70 enhances the survival of effector and memory CD8 T cells (14,15). Interestingly, it has been reported that the prosurvival effects of CD70 on CD8 T cell responses against influenza depend at least in part on the capacity of CD70 to prevent FasL upregulation on CD4 T cells and consequent Fas-dependent elimination of CD8 T cells (40). A role for CD70 in downregulation of CD8 T cell responses may have relevance for chronic infection, during which Ag and Ag-related survival signals persist, and continuous turnover of effector CD8 T cells occurs to ensure the replacement of senescent or ineffective T cells.…”

Section: Discussionmentioning

confidence: 56%

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CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

Wensveen

Unger

Kragten

et al. 2012

The Journal of Immunology

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Apoptosis plays an essential role in the removal of activated CD8 T cells that are no longer required during or postinfection. The Bim-dependent intrinsic pathway of apoptosis removes effector CD8 T cells upon clearance of viral infection, which is driven by withdrawal of growth factors. Binding of Fas ligand to Fas mediates activation-induced T cell death in vitro and cooperates with Bim to eliminate CD8 T cells during chronic infection in vivo, but it is less clear how this pathway of apoptosis is initiated. In this study, we show that the costimulatory TNFR CD27 provides a dual trigger that can enhance survival of CD8 T cells, but also removal of activated CD8 T cells through Fas-driven apoptosis. Using in vitro stimulation assays of murine T cells with cognate peptide, we show that CD27 increases T cell survival after stimulation with low doses of Ag, whereas CD27 induces Fas-driven T cell apoptosis after stimulation with high doses of Ag. In vivo, the impact of constitutive CD70-driven stimulation on the accumulation of memory and effector CD8 T cells is limited by Fas-driven apoptosis. Furthermore, introduction of CD70 signaling during acute infection with influenza virus induces Fas-dependent elimination of influenza-specific CD8 T cells. These findings suggest that CD27 suppresses its costimulatory effects on T cell survival through activation of Fas-driven T cell apoptosis to maintain T cell homeostasis during infection.

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Section: Discussionmentioning

confidence: 56%

“…Mice were sacrificed, and spleens were collected for analysis at the indicated days postinfection. LCMVspecific CD8 T cells were enumerated using allophycocyanin-conjugated tetramers of H-2D b containing the LCMV-derived peptide GP [33][34][35][36][37][38][39][40][41] KAVYNFATC (Sanquin Reagents). …”

Section: Lcmv Infectionmentioning

confidence: 99%

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

Wensveen

Unger

Kragten

et al. 2012

The Journal of Immunology

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“…Whether CD27/4-1BB triggering exerts similar effects on CD8 T cell differentiation when using vaccines that induce a higher degree of inflammation remains to be established. The outcome of disrupting the CD27-CD70 interaction on the generation of memory cells has been variable; some, but not all, studies showed a reduction in the number of memory CD8 T cells (12,35,36). It was suggested that CD27 signaling promotes the accumulation of MPECs only under conditions in which IL-12 is strongly induced (36), which may explain the conflicting data regarding the effect of CD27 signaling on the generation of memory cells.…”

Section: Discussionmentioning

confidence: 80%

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

Willoughby

Kerr

Rogel

et al. 2014

The Journal of Immunology

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The factors that determine differentiation of naive CD8 T cells into memory cells are not well understood. A greater understanding of how memory cells are generated will inform of ways to improve vaccination strategies. In this study, we analyzed the CD8 T cell response elicited by two experimental vaccines comprising a peptide/protein Ag and an agonist that delivers a costimulatory signal via CD27 or 4-1BB. Both agonists increased expansion of Ag-specific CD8 T cells compared with Ag alone. However, their capacity to stimulate differentiation into effector and memory cells differed. CD27 agonists promoted increased expression of perforin and the generation of short-lived memory cells, whereas stimulation with 4-1BB agonists favored generation of stable memory. The memory-promoting effects of 4-1BB were independent of CD4 T cells and were the result of programing within the first 2 d of priming. Consistent with this conclusion, CD27 and 4-1BB–stimulated CD8 T cells expressed disparate amounts of IL-2, IFN-γ, CD25, CD71, and Gp49b as early as 3 d after in vivo activation. In addition, memory CD8 T cells, generated through priming with CD27 agonists, proliferated more extensively than did 4-1BB–generated memory cells, but these cells failed to persist. These data demonstrate a previously unanticipated link between the rates of homeostatic proliferation and memory cell attrition. Our study highlights a role for these receptors in skewing CD8 T cell differentiation into effector and memory cells and provides an approach to optimize vaccines that elicit CD8 T cell responses.

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“…In contrast, the absence of 4-1BBL or OX40L on APC during reexposure to influenza has no effect on T-cell secondary expansion [29]. With regard to CD27, data are conflicting with evidence both for and against a role for this receptor during secondary T-cell expansion [12,15,[30][31][32][33].In this study, we investigated the role of CD27 costimulation during a secondary CD8 + T-cell response. Specifically, we show that maximal reactivation of memory CD8 + T cells by peptide and either anti-CD40 or the TLR agonists, polyI:C and LPS, requires CD70.…”

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confidence: 94%

CD27 costimulation contributes substantially to the expansion of functional memory CD8⁺T cells after peptide immunization

et al. 2013

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Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long-lived memory cells. The costimulatory receptor, CD27, is essential for optimal T-cell priming and memory differentiation in a variety of settings, although whether CD27 is similarly required during memory CD8 + T-cell reactivation remains controversial. We have used OVA and anti-CD40 to establish a memory CD8 + T-cell population and report here that their secondary expansion, driven by peptide and anti-CD40, polyI:C, or LPS, requires CD27. Furthermore, antigenic peptide and a soluble form of the CD27 ligand, CD70 (soluble recombinant CD70 (sCD70)), is sufficient for secondary memory CD8 + T-cell accumulation at multiple anatomical sites, dependent on CD80/86. Prior to boost, resting effector-and central-memory CD8 + T cells both expressed CD27 with greater expression on central memory cells. Nonetheless, both populations upregulated CD27 after TCR engagement and accumulated in proportion after boosting with Ag and sCD70. Mechanistically, sCD70 increased the frequency of divided and cytolytic memory T cells, conferred resistance to apoptosis and enabled retardation of tumor growth in vivo. These data demonstrate the central role played by CD27/70 during secondary CD8 + T-cell activation to a peptide Ag, and identify sCD70 as an immunotherapeutic adjuvant for antitumor immunity.Keywords: CD27 r CD70 r Memory r T cell r TLR r TNFRSF Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionT lymphocytes mediate immunity to infection and can protect against tumor growth. For full activation, T cells require TCR engagement and costimulatory signals provided predominantly Correspondence: Dr. Sarah L. Buchan e-mail: slb@soton.ac.uk through members of the Ig superfamily (e.g. CD28 and ICOS) and TNF receptor superfamily (TNFRSF; e.g. CD27 and 4-1BB). TNFRSF receptors signal via the NF-κB, MAPK, and PI3K pathways to facilitate cell cycle progression, upregulation of antiapoptotic Bcl-2 family members, secretion of cytokines, and expression of * These authors share co-authorship. * * These authors share senior co-authorship.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 3314-3323 Immunomodulation 3315 cytokine receptors leading to improved T-cell survival and proliferation. The existence of multiple TNFRSF members allows for tight temporal and spatial control of T-cell activation, regulated in part by the expression patterns of the receptors and their ligands [1]. Unlike many TNFRSF receptors, CD27 is highly expressed on naive CD4 + and CD8 + T cells and is further upregulated after TCR engagement [2]. The only known ligand for CD27/CD70 exhibits limited expression at rest but is upregulated on DC and B cells within 24 h of incubation with anti-CD40 or TLR agonists [3][4][5]. CD27/CD70 is therefore well poised to contribute to early T-cell activation events. Indeed, CD27 signals a...

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Late Signals from CD27 Prevent Fas-Dependent Apoptosis of Primary CD8+ T Cells

Cited by 73 publications

References 52 publications

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

CD27 costimulation contributes substantially to the expansion of functional memory CD8⁺T cells after peptide immunization

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Late Signals from CD27 Prevent Fas-Dependent Apoptosis of Primary CD8+ T Cells

Cited by 73 publications

References 52 publications

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

CD70-Driven Costimulation Induces Survival or Fas-Mediated Apoptosis of T Cells Depending on Antigenic Load

Differential Impact of CD27 and 4-1BB Costimulation on Effector and Memory CD8 T Cell Generation following Peptide Immunization

CD27 costimulation contributes substantially to the expansion of functional memory CD8+T cells after peptide immunization

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Resources

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CD27 costimulation contributes substantially to the expansion of functional memory CD8⁺T cells after peptide immunization