4-1BB co-stimulation enhances human CD8+ T cell priming by augmenting the proliferation and survival of effector CD8+ T cells

Laderach, Diego J.; Movassagh, Mojgan; Johnson, Anthony J.; Mittler, Robert S.; Galy, Anne

doi:10.1093/intimm/dxf080

Cited by 91 publications

(63 citation statements)

References 53 publications

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“…4-1BBL is expressed on activated antigen presenting cells [234]. 4-1BB signal also induces the anti-apoptotic proteins Bcl-x L and A1/Bfl-1 in T lymphocytes through an NF-κB dependent pathway [238][239][240]. However, during viral infection, CD4 + T cell function is unimpaired in 4-1BB -/-mice.…”

Section: Costimulatory Molecules and Anti-apoptotic Molecules In T Cellsmentioning

confidence: 99%

The role of apoptosis in the development and function of T lymphocytes

et al. 2005

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Apoptosis plays an essential role in T cell biology. Thymocytes expressing nonfunctional or autoreactive TCRs are eliminated by apoptosis during development. Apoptosis also leads to the deletion of expanded effector T cells during immune responses. The dysregulation of apoptosis in the immune system results in autoimmunity, tumorogenesis and immunodeficiency. Two major pathways lead to apoptosis: the intrinsic cell death pathway controlled by Bcl-2 family members and the extrinsic cell death pathway controlled by death receptor signaling. These two pathways work together to regulate T lymphocyte development and function.

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Section: Costimulatory Molecules and Anti-apoptotic Molecules In T Cellsmentioning

confidence: 99%

The role of apoptosis in the development and function of T lymphocytes

et al. 2005

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“…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-specific memory T cells in humans has not been addressed (19)(20)(21)(22)(23). In view of the evidence in mice that 4-1BBL is important in CD8 T cell memory (18), we set out to directly test the ability of 4-1BBL to stimulate antiviral cytotoxic memory T cells from humans.…”

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confidence: 99%

“…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-specific memory T cells in humans has not been addressed (19)(20)(21)(22)(23). In view of the evidence in mice that 4-1BBL is important in CD8 T cell memory (18), we set out to directly test the ability of 4-1BBL to stimulate antiviral cytotoxic memory T cells from humans.…”

mentioning

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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“…4-1BB also plays a marked role in the differentiation of effector memory CD8 þ T cells. 46 Although the 4-1BB signaling pathway was shown to lead to a preferential stimulation of CD8 þ compared with CD4 þ T cells, selective depletion of CD4 þ T-cell subpopulation in vivo with mAb resulted in the loss of the antitumor effect. 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.…”

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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4-1BB co-stimulation enhances human CD8+ T cell priming by augmenting the proliferation and survival of effector CD8+ T cells

Cited by 91 publications

References 53 publications

The role of apoptosis in the development and function of T lymphocytes

The role of apoptosis in the development and function of T lymphocytes

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

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

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