Provision of 4-1BB Ligand Enhances Effector and Memory CTL Responses Generated by Immunization with Dendritic Cells Expressing a Human Tumor-Associated Antigen

Wiethe, Carsten; Dittmar, Kurt E.J.; Doan, Tracy; Lindenmaier, Werner; Tindle, Robert W.

doi:10.4049/jimmunol.170.6.2912

Cited by 63 publications

(49 citation statements)

References 52 publications

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“…As shown here, we extend this approach by showing that autologous adherent monocytes can be converted into efficient APC with recombinant adenoviruses, a process that requires only an overnight incubation. Adenovirusmodified syngeneic APC could be used as immunogens directly (39,40), or they could be used to activate patient T cells ex vivo for adoptive immunotherapy, an approach that is being developed for HIV therapy (41). As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses

Bukczynski

Wen

Ellefsen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

100

106

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Effective adjuvants capable of inducing strong cytotoxic T cell responses in humans are lacking. In this study, we tested 4-1BBL as an adjuvant for activation of human memory antiviral CD8 T cell responses ex vivo. A recombinant replication-defective 4-1BBL adenovirus was used to convert autologous monocytes into efficient antigen-presenting cells after overnight incubation, bypassing the need to generate dendritic cells. Together with viral peptides, 4-1BBL led to robust memory responses of human EpsteinBarr virus-and influenza virus-specific cytotoxic T cells, with expansion of peptide-specific CD8 effector cells; up-regulation of Bcl-x L, granzyme A, and perforin; enhanced cytotoxic activity; and increased cytokine production. The response was significant even at a 100-fold lower peptide dose, compared with responses obtained with control adenovirus. Adenovirus-delivered B7.1 also expanded and activated virus-specific CD8 T cells, but 4-1BBL was more effective in driving the T cells toward a more fully differentiated CD27 ؊ effector state. Thus, 4-1BBL is a promising adjuvant for human memory CD8 T cells and will likely be most effective in the boost phase of a prime-boost strategy.E fficient activation of the cellular arm of the immune system requires a specific T cell antigen receptor signal delivered upon recognition of peptide͞MHC together with costimulatory signals. It has now been well established that dendritic cells are potent antigen-presenting cells (APC) for initiation of immune responses (1). Upon maturation, these cells up-regulate costimulatory molecules required for T cell activation. As a result, there is now considerable interest in the use of dendritic cells loaded with antigens as adjuvants for therapeutic vaccines (2, 3). A limitation of this approach is the need to derive the syngeneic dendritic cells in culture, a process that takes 7 days. In this report we describe the conversion of monocytes into efficient APC for activation of T cell memory responses by overnight incubation with recombinant adenoviruses expressing costimulatory molecules.Although the best characterized costimulatory molecule is CD28, recently other costimulatory molecules have been characterized (4-6). The emerging picture is that CD28 is important for the initial activation of an immune response and that other costimulatory ligand-receptor pairs act later to help sustain and diversify the response (4-6).4-1BB is an inducible costimulatory member of the tumor necrosis factor receptor family expressed on activated CD4 and CD8 T cells. Its ligand, 4-1BBL, is expressed on activated APC (6, 7). 4-1BB can enhance both the proliferation and the survival of murine CD4 and CD8 T cells (8)(9)(10)(11)(12)(13)(14). Recent evidence in mouse models suggests that 4-1BB͞4-1BBL interaction plays an important role in the memory CD8 T cell response to viruses (15-18).In humans, several studies have looked at the role of 4-1BBL or anti-4-1BB in polyclonal activation of T cells, but the specific role of 4-1BBL in activation of antigen-s...

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Section: Discussionmentioning

confidence: 99%

Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses

Bukczynski

Wen

Ellefsen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

100

106

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“…Although the lack of CD27 signaling results in suboptimal CD8 T cell responses (12,(14)(15)(16)(17), deliberate triggering of CD27 by administration of soluble rCD70 (18) or through transgenic expression of CD70 on DCs (19) prevents tolerance induced by injection of a peptide Ag and allows the generation of a population of effector and memory CD8 T cells. Similarly, 4-1BB triggering was shown to prevent peptide-induced CD8 T cell tolerance (20) and augment effector and memory responses following peptide or DC immunization (21)(22)(23).…”

mentioning

confidence: 99%

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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“…47 CD4 þ T cells may not be required during the generation of the initial immune response but may be important in the generation or maintenance of long-term memory responses. 48 It was found that the expansion and cytolytic function of tumor reactive CD8 þ T cells was enhanced by CD4 þ T cells. 49 Apart from T cells, other cells in the immune system have been shown to be influenced by 4-1BB:4-1BBL during immune responses.…”

Section: Role Of 4-1bb:4-1bbl In Primary Immune Responsesmentioning

confidence: 99%

Role of 4-1BB:4-1BB ligand in cancer immunotherapy

2003

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The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation. The CD28:B7 molecules are one of the best-studied costimulatory pathways, thought to be the main mechanism through which primary T-cell stimulation occurs. However, a number of molecules have been identified which serve to amplify and diversify the T-cell response, following initial Tcell activation. These include the more recently described 4-1BB:4-1BB ligand (4-1BBL) molecules. 4-1BB:4-1BBL are a member of the TNFR:TNF ligand family, which are expressed on T cells and antigen-presenting cells (APCs), respectively. Therapies utilizing the 4-1BB:4-1BBL signaling pathway have been shown to have antitumor effects in a number of model systems. In this paper, we focus on the 4-1BB:4-1BBL costimulatory molecules. In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer.

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Provision of 4-1BB Ligand Enhances Effector and Memory CTL Responses Generated by Immunization with Dendritic Cells Expressing a Human Tumor-Associated Antigen

Cited by 63 publications

References 52 publications

Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses

Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses

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

Role of 4-1BB:4-1BB ligand in cancer immunotherapy

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