Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

159

175

Oncolytic viruses can exert their antitumor activity via direct oncolysis or activation of antitumor immunity. Although reovirus is currently under clinical investigation for the treatment of localized or disseminated cancer, any potential immune contribution to its efficacy has not been addressed. This is the first study to investigate the ability of reovirus to activate human dendritic cells (DC), key regulators of both innate and adaptive immune responses. Reovirus induced DC maturation and stimulated the production of the proinflammatory cytokines IFN-α, TNF-α, IL-12p70, and IL-6. Activation of DC by reovirus was not dependent on viral replication, while cytokine production (but not phenotypic maturation) was inhibited by blockade of PKR and NF-κB signaling. Upon coculture with autologous NK cells, reovirus-activated DC up-regulated IFN-γ production and increased NK cytolytic activity. Moreover, short-term coculture of reovirus-activated DC with autologous T cells also enhanced T cell cytokine secretion (IL-2 and IFN-γ) and induced non-Ag restricted tumor cell killing. These data demonstrate for the first time that reovirus directly activates human DC and that reovirus-activated DC stimulate innate killing by not only NK cells, but also T cells, suggesting a novel potential role for T cells in oncolytic virus-induced local tumor cell death. Hence reovirus recognition by DC may trigger innate effector mechanisms to complement the virus’s direct cytotoxicity, potentially enhancing the efficacy of reovirus as a therapeutic agent.

Section: Discussionmentioning

confidence: 99%

Section: Reo-dc Stimulate Innate Antitumor Activity In T Cellsmentioning

confidence: 99%

Reovirus Activates Human Dendritic Cells to Promote Innate Antitumor Immunity

Errington

Steele

Prestwich

et al. 2008

159

175

“…upon short term culture of T cells with cytokines (22,23). We therefore set out to address whether our cytokine-secreting OK-DC could similarly stimulate innate T cell functions, including cytotoxicity.…”

Section: Ok432 Enhances DC Migrationmentioning

confidence: 99%

OK432-Activated Human Dendritic Cells Kill Tumor Cells via CD40/CD40 Ligand Interactions

Hill

Errington

Steele

et al. 2008

In vivo, dendritic cells (DC) are programmed to orchestrate innate and adaptive immunity in response to pathogen-derived “danger” signals. Under particular circumstances, DC can also be directly cytotoxic against tumor cells, potentially allowing them to release tumor associated Ags from dying cells and then prime antitumor immunity against them. In this study, we describe the innate characteristics of DC (OK-DC) generated in vitro after exposure of immature human myeloid-derived DC to OK432, a penicillin-inactivated and lyophilized preparation of Streptococcus pyrogenes. OK-DC produced proinflammatory cytokines, stimulated autologous T cell proliferation and IFN-γ secretion, expressed CCR7, and migrated in response to MIP-3β. Moreover, OK-DC displayed strong, specific cytotoxicity toward tumor cell targets. This cytotoxicity was associated with novel, OK432-induced up-regulation of CD40L on the cell surface of OK-DC, and was absolutely dependent on expression of CD40 on the tumor targets. These data demonstrate that maturation of human DC with OK432, an adjuvant suitable for clinical use, induces direct tumor cell killing by DC, and describes a novel CD40/CD40L-mediated mechanism for specific DC antitumor cytotoxicity.

“…In vitro studies have shown that high concentrations of IL-15 can induce cellular proliferation and transcription of effector molecules such as IFN-␥ and granzyme B (grB) (14,15). Additionally, soluble IL-15 can augment anti-CD3 -induced activation and cytokine production of both mouse and human CD8 ϩ T cells (16 -19).…”

mentioning

confidence: 99%

IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

Kokaji

Hockley

Kane

2008

Although the adaptive immune system has a remarkable ability to mount rapid recall responses to previously encountered pathogens, the cellular and molecular signals necessary for memory CD8+ T cell reactivation are poorly defined. IL-15 plays a critical role in memory CD8+ T cell survival; however, whether IL-15 is also involved in memory CD8+ T cell reactivation is presently unclear. Using artificial Ag-presenting surfaces prepared on cell-sized microspheres, we specifically addressed the role of IL-15 transpresentation on mouse CD8+ T cell activation in the complete absence of additional stimulatory signals. In this study we demonstrate that transpresented IL-15 is significantly more effective than soluble IL-15 in augmenting anti-CD3ε-induced proliferation and effector molecule expression by CD8+ T cells. Importantly, IL-15 transpresentation and TCR ligation by anti-CD3ε or peptide MHC complexes exhibited synergism in stimulating CD8+ T cell responses. In agreement with previous studies, we found that transpresented IL-15 preferentially stimulated memory phenotype CD8+ T cells; however, in pursuing this further, we found that central memory (TCM) and effector memory (TEM) CD8+ T cells responded differentially to transpresented IL-15. TCM CD8+ T cells undergo Ag-independent proliferation in response to transpresented IL-15 alone, whereas TEM CD8+ T cells are relatively unresponsive to transpresented IL-15. Furthermore, upon Ag-specific stimulation, TCM CD8+ T cell responses are enhanced by IL-15 transpresentation, whereas TEM CD8+ T cell responses are only slightly affected, both in vitro and in vivo. Thus, our findings distinguish the role of IL-15 transpresentation in the stimulation of distinct memory CD8+ T cell subsets, and they also have implications for ex vivo reactivation and expansion of Ag-experienced CD8+ T cells for immunotherapeutic approaches.