4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses

Shuford, Walter W.; Klussman, Kerry; Tritchler, Douglas D.; Loo, Deryk; Chalupny, Jan; Siadak, Anthony W.; Brown, T J; Emswiler, John; Raecho, Hong; Larsen, Christian; Pearson, Thomas C.; Ledbetter, Jeffrey A.; Aruffo, Alejandro; Mittler, Robert S.

doi:10.1084/jem.186.1.47

Cited by 712 publications

(654 citation statements)

References 11 publications

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“…4-1BB (CD137) is a receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily (Goodwin et al, 1993;Kwon et al, 1987;Lotz et al, 1996;Setareh et al, 1995) which is expressed in an activation-dependent manner on T cells Pollok et al, 1993;Schwarz et al, 1996;Shuford et al, 1997) and constitutively on CD4 + CD25 + regulatory T cells (McHugh et al, 2002). Although 4-1BB is mainly involved in regulating activated T lymphocyte functions, expression of 4-1BB has been noted on non-T cells such as B cells, monocytes, macrophages, dendritic cells, eosinophils, and neutrophils (Futagawa et al, 2002;Heinisch et al, 2000;Schwarz et al, 1995;Watts et al, 2005;Wilcox et al, 2002;Yoon et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

Kim

Kwon

2011

Molecules and Cells

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The expression of 4-1BB has been known to be dependent on T cell activation. Recent studies have, however, revealed that 4-1BB expression is not restricted to T cells. We sought to determine the molecular basis for the differential gene expression. Here we report the expression pattern of two mouse 4-1BB transcripts, type I and type II. Whereas the type I transcript was specifically expressed on immune organ as previously reported, the type II transcript was ubiquitously expressed in tissues and various cell lines. However, both type I and type II transcript were highly induced on activated T cells. Primer extension assay of the two 4-1BB transcripts suggested that mouse 4-1BB had more than two transcripts. Using luciferase assay we have identified three promoter regions (PI, PII and PIII), which located on upstream region of second exon 1, first exon 1, and exon 2, respectively. In particular, the type I transcript was preferentially induced when naïve T cells are stimulated by anti-CD3 monoclonal antibody (mAb) since NF-κB specifically binds to the putative NF-κB element of PI. We have also shown that a splice variant, in which the transmembrane domain was deleted, could inhibit 4-1BB signaling. The splicing variant was highly induced by TCR stimulation. Our results reveal 4-1BB also has a negative regulation system through soluble 4-1BB produced from a splice variant induced under activation conditions.

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Section: Introductionmentioning

confidence: 99%

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

Kim

Kwon

2011

Molecules and Cells

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“…Extensive evidence supports the role of 4-1BB as a costimulatory molecule that can function independently of CD28 [9,13,14] to activate T cells [10,15,16]. 4-1BB can influence cytokine production, proliferation and survival of T cells in vitro and in vivo [8][9][10][16][17][18][19][20][21][22][23][24]. Stimulatory anti-4-1BB antibodies show a preferential role for 4-1BB in CD8 + T cell activation in vitro [20].…”

Section: Introductionmentioning

confidence: 99%

“…4-1BB can influence cytokine production, proliferation and survival of T cells in vitro and in vivo [8][9][10][16][17][18][19][20][21][22][23][24]. Stimulatory anti-4-1BB antibodies show a preferential role for 4-1BB in CD8 + T cell activation in vitro [20]. However, purified CD4 T cells as well as antigen-specific MHC class II-restricted TCR transgenic cells can clearly respond to 4-1BBL in vitro [15,17,22,25].…”

Section: Introductionmentioning

confidence: 99%

Expression and function of 4‐1BB during CD4 versus CD8 T cell responses in vivo

Dawicki

Watts

2004

Eur J Immunol

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4-1BBL -/-mice have a defect in recall CD8 + T cell responses to viruses, whereas CD4 + T cell responses to virus are unimpaired in these mice. In contrast, both CD4 + and CD8 + T cells respond to 4-1BB ligand (4-1BBL) in vitro. To clarify the role of 4-1BB/4-1BBL in CD4 + versus CD8 + T cell responses in vivo, we compared CD4 (OT-II) and CD8 (OT-I) TCR transgenic T cells responding to the same antigen in an in vivo adoptive transfer model in 4-1BBL +/+ versus 4-1BBL -/-mice. During primary and secondary responses, expression of 4-1BB on in vivo-activated TCR transgenic T cells was earlier and more transient than previously observed in vitro, correlating with expression of the early activation antigen CD69 and preceding the transition to the CD44 hi state. Although 4-1BB is expressed early in the primary response, there was no effect of 4-1BBL deficiency on initial CD8 T cell expansion and only a minor effect on initial CD4 T cell expansion. The major effect of 4-1BB/4-1BBL interaction is on the T cell recall response. This is due to effects of 4-1BBL on maintenance of T cell numbers at the end of the primary response with additional effects of 4-1BBL on secondary expansion of T cells.

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“…40 Although stimulation of the 4-1BB:4-1BBL signaling pathway leads to both CD4 þ and CD8 þ T-cell activation, 19,41,42 evidence has shown that it caused the preferential expansion of CD8 þ T cells. Shuford et al 43 used mAbs to show that 4-1BB signaling markedly enhanced interferon-g production from CD8 þ T cells and that the a-4-1BB mediated proliferation of CD8 þ T cells appeared to be IL-2 independent. Use of a-4-1BB Ab, in vitro, to stimulate CD8 þ T cells with downregulated CD28 showed that CD28 expression was restored, while expression of the memory marker CD45RO and CC chemokine receptor 6 (CCR6) and the content of granzyme B were also enhanced.…”

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 Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses

Cited by 712 publications

References 11 publications

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

Regulation of Mouse 4-1BB Expression: Multiple Promoter Usages and a Splice Variant

Expression and function of 4‐1BB during CD4 versus CD8 T cell responses in vivo

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

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