A Switch in Costimulation from CD28 to 4-1BB during Primary versus Secondary CD8 T Cell Response to Influenza In Vivo

Bertram, Edward M.; Dawicki, Wojciech; Sedgmen, Bradley J; Bramson, Jonathan L.; Lynch, David H.; Watts, Tania H.

doi:10.4049/jimmunol.172.2.981

Cited by 114 publications

(118 citation statements)

References 53 publications

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“…However, i.p. infection of influenza virus in 4-1BBL Ϫ/Ϫ mice showed normal primary CD8 responses, but in this case with impaired memory formation (25)(26)(27). Collectively, these data suggest that OX40-OX40L and 4-1BB-4-1BBL interactions can provide enhancing signals, but their interaction is not always necessary to priming of CD8 T cells.…”

Section: Functional Dichotomy Between Ox40 and 4-1bb Inmentioning

confidence: 73%

“…In opposition to some of the experiments with anti-4-1BB, all studies of 4-1BBL Ϫ/Ϫ mice have either revealed no role for this ligand in initial CD8 priming, or suggested that 4-1BB/4-1BBL interactions play a positive, enhancing role, largely at a late stage of the CD8 T cell response when memory has formed or when memory is beginning to develop (23)(24)(25)(26)(27). Our studies represent the first to specifically address how the lack of 4-1BB on a CD8 cell affects its initial response and clearly show that without 4-1BB, CD8 cells are hyperresponsive to Ag in both primary and secondary responses, at least when provided via adenovirus.…”

Section: Discussionmentioning

confidence: 99%

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Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Lee

Park

Song

et al. 2006

The Journal of Immunology

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Members of the TNFR family are thought to deliver costimulatory signals to T cells and modulate their function and survival. In this study, we compare the role of two closely related TNFR family molecules, OX40 and 4-1BB, in generating effector CD8 T cells to Ag delivered by adenovirus. OX40 and 4-1BB were both induced on responding naive CD8 T cells, but 4-1BB exhibited faster and more sustained kinetics than OX40. OX40-deficient CD8 T cells initially expanded normally; however, their accumulation and survival at late times in the primary response was significantly impaired. In contrast, 4-1BB-deficient CD8 T cells displayed hyperresponsiveness, expanding more than wild-type cells. The 4-1BB-deficient CD8 T cells also showed enhanced maturation attributes, whereas OX40-deficient CD8 T cells had multiple defects in the expression of effector cell surface markers, the synthesis of cytokines, and in cytotoxic activity. These results suggest that, in contrast to current ideas, OX40 and 4-1BB can have a clear functional dichotomy in modulating effector CD8 T cell responses. OX40 can positively regulate effector function and late accumulation/survival, whereas 4-1BB can initially operate in a negative manner to limit primary CD8 responses.

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Section: Functional Dichotomy Between Ox40 and 4-1bb Inmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Lee

Park

Song

et al. 2006

The Journal of Immunology

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“…[25]. These factors are also known to affect T memory/effector cell activation [26,27]. Consequently, one might expect that different antigen doses (constituting Signal 1) will be required for T cell triggering upon antigen recognition on different APC.…”

Section: Similar Per Cell Ifn-γ Productivity Of Cd4 Cells Stimulated mentioning

confidence: 99%

The secretory IFN-γ response of single CD4 memory cells after activation on different antigen presenting cell types

Ott¹,

Tary‐Lehmann²,

Lehmann³

2007

Clinical Immunology

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It is unknown to what extent the heterogeneity of antigen presenting cells (APC) influences the IFN-γ response of CD4 memory cells. We restimulated DO11.10 T cell receptor (TCR)-transgenic cells and wild-type CD4 memory cells with OVA-peptide 323 -339 presented on purified dendritic cells (DC), macrophages, and B cells. Using IFN-γ ELISPOT assays we measured the number of cytokine producing T cells and the amount of cytokine produced by individual T cells at different time points after antigen encounter. The data showed that, when CD4 cells recognized antigen on DC, the induction of cytokine production was accelerated compared to macrophages and B cells. In contrast, the per-cell cytokine productivity was independent of the type of APC by which the T cells were restimulated. Moreover, the peptide concentration required for CD4 cell activation was comparable for the different APC. The data suggest that DC induce cytokine production in memory cells with accelerated activation kinetics, whereas 24 h of antigen stimulation on DC, macrophages, and B cells results in comparable levels of T cell activation. These data have implications for the understanding of T cell memory responses when T cells re-encounter antigen on different APC as well as for the monitoring of memory T cell responses ex vivo.

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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)(16)(17)(18).…”

mentioning

confidence: 99%

“…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. The results show that 4-1BBL-mediated costimulation is highly effective in expanding and activating T cell memory responses to influenza virus and Epstein-Barr virus (EBV) and does so with faster kinetics than B7.1.…”

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.

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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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A Switch in Costimulation from CD28 to 4-1BB during Primary versus Secondary CD8 T Cell Response to Influenza In Vivo

Cited by 114 publications

References 53 publications

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

Functional Dichotomy between OX40 and 4-1BB in Modulating Effector CD8 T Cell Responses

The secretory IFN-γ response of single CD4 memory cells after activation on different antigen presenting cell types

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

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