Effect of IL-18 on Expansion of γδ T Cells Stimulated by Zoledronate and IL-2

Abstract

Zoledronate (Zol) has recently been shown to expand gammadelta T cells that play important roles in host defenses against infection and tumors. In this study, we examined effects of interleukin-18 (IL-18) on expansion of gammadelta T cells in human peripheral blood mononuclear cells (PBMCs) stimulated by Zol and IL-2. The expansion of gammadelta T cells stimulated by Zol and IL-2 was strongly promoted by exogenous IL-18, and to the contrary, inhibited by neutralizing anti-IL-18 receptor antibody. The gammadelta T cells that expanded in the presence of Zol, IL-2, and IL-18 exhibited the phenotype of effector memory cells characterized by CD44 (+), CD27 (-), and CD45RA (-). In addition, they expressed NKG2D, perforin, CD94, CD25, and CD122, and 15% to 40% of them were positive for CD56. Incubation of gammadelta T cells in the presence with IL-18 produced GM-CSF, IFN-gamma, and TNF-alpha at much higher levels than those incubated without IL-18. They showed strong cytotoxicity against tumor cells including mesothelioma cells and inhibited growth of xenograft of mesothelioma in mice. These observations indicate that IL-18 can efficiently promote expansion of gammadelta T cells with potent antitumor activity.

Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire

“…Both zoledronate ( Fig. 4A) and HMB-PP ( (41). High expression of the IL-18 receptor (IL-18R) (see below) on fetal Vγ9Vδ2 T cells could contribute to this expansion and might make this subset more receptive to IL-18 in early life (27).…”

Essential Requirements of Zoledronate-Induced Cytokine and γδ T Cell Proliferative Responses

“…IL-18, which is a stress-related, caspase-1-processed cytokine (31), was implicated in zoledronateinduced NK cell and gd T cell activation (29) and was shown to costimulate zoledronate-induced, IL-2-driven gd T cell expansion (32). A population of CD56 bright CD11c + NK cells was postulated to mediate the stimulatory effect of IL-18 in zoledronate-induced gd T cell expansion (33).…”

Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18

“…Therefore, it is important that aPD-1/PD-L1-and/or aCTLA-4-based therapies are analyzed in a wider range of patients. Because effective antitumor responses require immune activation as well as immune checkpoint blockade, we examined the synergistic effect of IL18, which was demonstrated to enhance effector functions of immune cells (25,26,38,39) on the survival rate of preimplanted mice receiving aPD-L1 and/or aCTLA-4. To develop an in vivo model of peritoneal dissemination, mice were intraperitoneally inoculated with the CT-26 colon carcinoma cells.…”

“…In addition, they are linked to cellular metabolism and to events such as pyroptosis and mitochondria autophagy, regulating cell viability. IL18 may thus play an important role in the responses to cellular stress and is involved in maintenance of energy metabolism homeostasis and in quality control of organelles, leading to cell survival and expansion of activated lymphocytes (25)(26)(27).…”

“…þ CTLs, and gd T cells which express IL18 receptors a/b chains and receptors containing immunoreceptor tyrosine-based activation motif (ITAM), and produce IFNg (23)(24)(25)(26)(27). In humans, IL18 promotes the expansion of CD56 bright CD11c þ HLA-DR þ helper NK cells, which may be a human counterpart of mouse precursors of mature natural killer (pre-mNK) cells, previously referred to as IFN-producing killer dendritic cells (28,29).…”