Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

Perera, Liyanage P.; Goldman, Carolyn K.; Waldmann, Thomas A.

doi:10.1073/pnas.081080298

Cited by 33 publications

(25 citation statements)

References 35 publications

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“…Thus, cell surface IL-15 can activate Rac3, an ability that its soluble counterpart lacks. These data reinforce the idea proposed by ourselves (24) and others (23,33) that cell surface IL-15 may function differently than its soluble counterpart and provide some new insight into how this functional difference may manifest itself at the cellular level.…”

Section: Il-15 Functions As a Receptor To Activate Rho Family Gtpasessupporting

confidence: 76%

Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling

Neely¹,

Epelman

Ling³

et al. 2004

The Journal of Immunology

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IL-15 is a short chain, four-α helix cytokine that shares some biological function with IL-2. One striking difference between IL-2 and IL-15 is the ability of monocytes to express IL-15 on their cell surface after activation. In the current study we have investigated the ability of human monocyte cell surface IL-15 to participate in reverse signaling. Cross-linking anti-IL-15 Abs were used as a surrogate ligand for surface IL-15 engagement. Ligation of cell surface-expressed IL-15 induced monocyte adhesion that required the activity of small m.w. GTPases. Reverse signals through surface IL-15 activated the Rho-GTPase Rac3. In addition, engagement of cell surface IL-15 was found to activate a number of signaling pathways, including both extracellular signal-regulated kinase 1/2 and p38, and resulted in the secretion of IL-8. IL-8 production required mitogen-activated protein kinase activity. Thus, the current study has established that cell surface IL-15 is more than just a ligand; it can function as a receptor and participate in reverse signaling that results in cellular adhesion and production of inflammatory cytokines.

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Section: Il-15 Functions As a Receptor To Activate Rho Family Gtpasessupporting

confidence: 76%

Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling

Neely¹,

Epelman

Ling³

et al. 2004

The Journal of Immunology

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“…Both vPE16 and vPE16-IL15 were completely undetectable in both depleted and undepleted mice by day 11 in all three tissues. This is consistent with clearance of vaccinia being dependent on IFN␥ (17,18), which can be made in large quantity by NK cells, which are increased by IL-15 independent of CD4 ϩ T cell help.…”

Section: Il-15 Substitutes For Cd4 ؉ Help In Cd8 ؉ T Cell Priming Forsupporting

confidence: 65%

IL-15 as a mediator of CD4 ⁺ help for CD8 ⁺ T cell longevity and avoidance of TRAIL-mediated apoptosis

Perera

Terabe

et al. 2008

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

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127

128

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Antigen-specific CD8 ϩ T cells can be programmed in the immune induction phase (3-5). CD4 ϩ help is needed for induction of long-lived memory CD8ϩ T cells (6, 7). The results of early programming are more profound in secondary responses: CD8 ϩ T cells primed in the absence of CD4 ϩ helper T cells undergo tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and show poor long term memory (8, 9). Thus, understanding the mechanisms by which help from CD4 ϩ T cells prevents CD8 ϩ T cell death and enhances the maintenance of memory CD8 ϩ T cells is critical for developing new vaccines.In addition to the maintenance of CD8 ϩ memory T cells (10-15), we previously found that additional IL-15 provided by a vaccine vector only during priming induced long-lived memory CD8 ϩ T cells (5) and contributed to the long-term avidity maturation of CD8 ϩ T cells (16). These findings suggest that IL-15 contributes to programming of CD8 ϩ T cells to be long-lived cells that can further expand on reexposure to antigen. Therefore, we hypothesized that CD8 ϩ T cells programmed with IL-15 only during priming, even in the absence of CD4 ϩ helper T cells, may overcome TRAIL-mediated apoptosis during secondary responses and persist longer. We also hypothesized that one mechanism by which CD4 ϩ helper T cells help CD8 ϩ T cells is to stimulate IL-15 production by the antigen presenting cells (APCs), including dendritic cells (DCs).Here, we show that IL-15 provided by the vaccine can replace CD4 ϩ helper T cells in inducing long-lasting antigen-specific CD8 ϩ T cells that can efficiently respond to secondary responses.Conversely, help was less effective when DCs did not produce IL-15. Thus, we conclude that IL-15 codelivered with vaccines can overcome CD4 ϩ helper T cell deficiency and that IL-15 may be one mediator of help. These new findings will be important for developing new vaccines against cancers and viral infections, especially those such as HIV that result in diminished CD4 ϩ T cell help. Results IL-15 Substitutes for CD4 ؉ Help in CD8 ؉ T Cell Priming for Long-LivedMemory. To test whether IL-15 can substitute for CD4 ϩ T cells in the induction of longer-lived antigen-specific CD8 ϩ T cells, animals, either CD4-depleted or undepleted, were immunized with recombinant vaccinia viruses expressing HIVgp160 (vPE16) or .CD4 ϩ T cell-undepleted animals immunized with vPE16 maintained P18-I10-specific CD8 ϩ T cells (measured directly ex vivo without restimulation) for 1 year (Fig. 1A). Animals immunized with vPE16-IL-15 had a higher percentage of long-lasting memory CD8 ϩ T cells than those without IL-15 (percentage of peak response remaining, 23% vs. 16%), indicating that IL-15 provided by the vaccine vector contributes to the enhanced induction of long-lasting memory CD8 ϩ CTL in WT animals and that endogenous IL-15 may be limiting. In contrast, in CD4-depleted animals, the majority of the CD8 ϩ T cells induced by vPE16 disappeared shortly after the primary response, with Ͻ1% of the peak response remaining at...

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“…Numerous studies have addressed the role of IL-2 as a potent vaccine adjuvant, particularly for both CD4 ϩ and CD8 ϩ T cell responses. Both VV-IL-2 (27) and VV-IL-15 (28) are also known to enhance natural immunity in a short period. However, the effects of IL-2 and IL-15 in antigen-specific humoral immune responses remain less clear.…”

Section: Resultsmentioning

confidence: 99%

Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity

Berzofsky

Burke

et al. 2003

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

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173

142

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Vaccine efficacy is determined largely by cellular and humoral immunity as well as long-lasting immunological memory. IL-2 and IL-15 were evaluated in vaccinia vectors expressing HIV gp160 for the establishment of an effective vaccine strategy. Both IL-2 and IL-15 in the vaccinia vector induced strong and long-lasting antibody-mediated immunity as well as a short-term cytotoxic T cell response against HIV gp120. In addition, IL-15 also supported robust CD8 ؉ T cell-mediated long-term immunity, whereas the CD8 ؉ T cell-mediated immunity induced by IL-2 was short-lived. Moreover, we found that the cytokine milieu at the time of priming had surprisingly persistent effects on the character of the memory CD8 T cells long afterward with respect to their fate, functional activities, cytokine receptor expression, and antigen-independent proliferation.

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Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

Cited by 33 publications

References 35 publications

Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling

Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling

IL-15 as a mediator of CD4 ⁺ help for CD8 ⁺ T cell longevity and avoidance of TRAIL-mediated apoptosis

Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity

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Comparative assessment of virulence of recombinant vaccinia viruses expressing IL-2 and IL-15 in immunodeficient mice

Cited by 33 publications

References 35 publications

Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling

Monocyte Surface-Bound IL-15 Can Function as an Activating Receptor and Participate in Reverse Signaling

IL-15 as a mediator of CD4 + help for CD8 + T cell longevity and avoidance of TRAIL-mediated apoptosis

Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity

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IL-15 as a mediator of CD4 ⁺ help for CD8 ⁺ T cell longevity and avoidance of TRAIL-mediated apoptosis