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IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.
Copyright © 2015 by The American Association of Immunologists, Inc.
OBJECTIVE - The role of natural killer (NK) cells in regulating multiple sclerosis (MS) is not well understood. Additional studies with NK cells might provide insight into the mechanism of action of MS therapies such as daclizumab, an antibody against the interleukin (IL)-2R α-chain, which induces expansion of CD56(bright) NK cells.
METHODS - In a relapsing-remitting form of the experimental autoimmune encephalomyelitis (EAE) model of MS induced in SJL mice, we expanded NK cells with IL-2 coupled with an anti-IL-2 monoclonal antibody (mAb) and evaluated the effects of these NK cells on EAE. Further, we investigated the effect of the human version of IL-2/IL-2 mAb on NK cells from MS patients and its effect on central nervous system (CNS) inflammation and pathology in a human-mouse chimera model and assessed the underlying mechanisms.
RESULTS - IL-2/IL-2 mAb dramatically expands NK cells both in the peripheral lymphoid organs and in the CNS, and attenuates CNS inflammation and neurological deficits. Disease protection is conferred by CNS-resident NK cells. Importantly, the human version of IL-2/IL-2 mAb restored the defective CD56(+) NK cells from MS patients in a human-mouse chimera model. Both the CD56(bright) and CD56(dim) subpopulations were required to attenuate disease in this model.
INTERPRETATION - These findings unveil the immunotherapeutic potential of NK cells, which can act as critical suppressor cells in target organs of autoimmunity. These results also have implications to better understand the mechanism of action of daclizumab in MS.
Copyright © 2011 American Neurological Association.
PURPOSE - The combination of systemic multiagent chemotherapy (5-fluorouracil + cisplatin) and tumor irradiation is standard of care for head and neck squamous cell carcinoma (HNSCC). Furthermore, it has been shown that sublethal doses of radiation or chemotherapeutic drugs in diverse cancer types may alter the phenotype or biology of neoplastic cells, making them more susceptible to CTL-mediated cytotoxicity. However, little is known about the potential synergistic effect of drug plus radiation on CTL killing. Here, we examined whether the combination of two chemotherapeutics and ionizing radiation enhanced CTL-mediated destruction of HNSCC more so than either modality separately, as well as the basis for the enhanced tumor cell lysis.
EXPERIMENTAL DESIGN - Several HNSCC cell lines with distinct biological features were treated with sublethal doses of cisplatin and 5-fluorouracil for 24 hours and with 10-Gy irradiation. Seventy-two hours postirradiation, tumor cells were exposed to an antigen-specific CD8+ CTL directed against carcinoembryonic antigen or MUC-1.
RESULTS - In three of three tumor cell lines tested, enhanced CTL activity was observed when the two modalities (chemotherapy and radiation) were combined as compared with target cells exposed to either modality separately. CTL-mediated lysis was MHC restricted and antigen specific and occurred almost entirely via the perforin pathway. Moreover, the combination treatment regimen led to a 50% reduction in Bcl-2 expression whereas single modality treatment had little bearing on the expression of this antiapoptotic gene.
CONCLUSIONS - Overall, these results reveal that (a) CTL killing can be enhanced by combining multiagent chemotherapy and radiation and (b) combination treatment enhanced or sensitized HNSCC to the perforin pathway, perhaps by down-regulating Bcl-2 expression. These studies thus form the rational basis for clinical trials of immunotherapy concomitant with the current standard of care of HNSCC.
Although major histocompatibility complex (MHC) class II-restricted CD4 T cells are well appreciated for their contribution to peripheral tolerance to tissue allografts, little is known regarding MHC class I-dependent reactivity in this process. Here we show a crucial role for host MHC class I-dependent NK cell reactivity for allograft tolerance in mice induced through either costimulation blockade using CD154-specific antibody therapy or by targeting LFA-1 (also known as CD11a). Tolerance induction absolutely required host expression of MHC class I, but was independent of CD8 T cell-dependent immunity. Rather, tolerance required innate immunity involving NK1.1(+) cells, but was independent of CD1d-restricted NKT cells. Therefore, NK cells seem to be generally required for induction of tolerance to islet allografts. Additional studies indicate that CD154-specific antibody-induced allograft tolerance is perforin dependent. Notably, NK cells that are perforin competent are sufficient to restore allograft tolerance in perforin-deficient recipients. Together, these results show an obligatory role for NK cells, through perforin, for induction of tolerance to islet allografts.
Primary immunization of healthy adults with vaccinia virus induces a local vesicle or "take" in the majority of vaccinees that previously has been shown to correlate with protection against smallpox. However, the immunologic mechanisms underlying this protective response in humans are not well characterized. We have studied human CD8+ T cells for the expression patterns of phenotypic markers and cytolytic effector molecules before and after primary smallpox immunization using nine-color polychromatic flow cytometry. One month after immunization, vaccinees developed vaccinia virus-specific CD8+ T cells with an effector cell phenotype containing both granzyme A and granzyme B. One year after immunization, we found a significant decrease in granzyme B containing cells and an increased memory cell phenotype in virus-specific CD8+ T cells. Perforin was rarely expressed directly ex vivo, but was highly expressed after Ag-specific activation in vitro. Together, these data suggest an important role for effector CD8+ T cells in controlling poxvirus infection, and have implications for our understanding of human CD8+ T cell differentiation.
Malaria, caused by infection with Plasmodium spp., is a life cycle-specific disease that includes liver injury at the erythrocyte stage of the parasite. In this study, we have investigated the mechanisms underlying Plasmodium berghei-induced liver injury, which is characterized by the presence of apoptotic and necrotic hepatocytes and dense infiltration of lymphocytes. Although both IL-12 and IL-18 serum levels were elevated after infection, IL-12-deficient, but not IL-18-deficient, mice were resistant to liver injury induced by P. berghei. Neither elevation of serum IL-12 levels nor liver injury was observed in mice deficient in myeloid differentiation factor 88 (MyD88), an adaptor molecule shared by Toll-like receptors (TLRs). These results demonstrated a requirement of the TLR-MyD88 pathway for induction of IL-12 production during P. berghei infection. Hepatic lymphocytes from P. berghei-infected wild-type mice lysed hepatocytes from both uninfected and infected mice. The hepatocytotoxic action of these cells was blocked by a perforin inhibitor but not by a neutralizing anti-Fas ligand Ab and was up-regulated by IL-12. Surprisingly, these cells killed hepatocytes in an MHC-unrestricted manner. However, CD1d-deficient mice that lack CD1d-restricted NK T cells, were susceptible to liver injury induced by P. berghei. Collectively, our results indicate that the liver injury induced by P. berghei infection of mice induces activation of the TLR-MyD88 signaling pathway which results in IL-12 production and activation of the perforin-dependent cytotoxic activities of MHC-unrestricted hepatic lymphocytes.
The glycolipid alpha -galactosylceramide (alpha -GalCer), which is presented by CD1d and specifically activates Valpha 14 NKT cells, exerts a potent anti-metastatic effect when administered in vivo. In this study, we demonstrated that alpha -GalCer administration led to rapid elimination of NKT cells by apoptosis in the liver and spleen, after they produced IFN-gamma and IL-4. In contrast, a more prolonged secretion of IFN-gamma was observed by liver and splenic NK cells after alpha -GalCer administration. Cytotoxic activity of liver mononuclear cells was not augmented 3h after alpha -GalCer administration, but was increased at 24 h when NKT cells were mostly depleted. The alpha -GalCer-induced cytotoxic activity was abolished in IFN-gamma -deficient and NK cell-depleted mice as well as CD1-deficient mice, suggesting that the alpha -Galcer-induced cytotoxicity was mainly mediated by IFN-gamma -activated NK cells. While the alpha -GalCer-induced cytotoxicity in vitro was mostly perforin dependent, anti-metastatic effect of alpha -GalCer was impaired in NK cell-depleted or IFN-gamma -deficient mice but not in perforin-deficient mice. Collectively, these results indicated that the anti-metastatic effect of alpha -GalCer is mainly mediated by NK cells, which are activated secondarily by IFN-gamma produced by alpha -GalCer-activated NKT cells, in a perforin-independent manner.
CD1-dependent NK1+ T cells rapidly produce IL-4 upon stimulation through the TCR. These cells may therefore play an important role in the initiation of Th2 responses. Here, we show that NK1+ T cells constitutively express receptors for IL-12 and IFN-gamma, and that IL-12 induces production of perforin in these cells. Moreover, while IL-12 induces high levels of IFN-gamma and cytotoxic activity of hepatic or splenic mononuclear cells against tumor cells, this effect of IL-12 is significantly reduced in CD1-deficient mice with impaired NK1+ T cells development. These results indicate that NK1+ T cells play a critical role in IL-12-induced production of IFN-gamma to initiate Th1 immune responses and as IL-12-induced cytotoxic effector cells to initiate antitumor immunity.
The roles of cytolytic regulatory mechanisms in the immune system of lupus-prone mice were examined in perforin-deficient animals bearing functional or defective (lpr) Fas Ag (CD95). Perforin-deficient Fas+ animals developed accelerated autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody production, and immune deposit-related end-organ disease compared with perforin-intact counterparts. In comparison, perforin-deficient lpr animals had accelerated mortality compared with perforin-intact lpr mice, associated with the abnormal accumulation of CD3+CD4-CD8- alphabeta T cells in conjunction with unaltered hypergammaglobulinemia, autoantibody production, and immune complex renal disease. These results indicate that cytolytic lymphoid regulation plays critical roles in the immune homeostasis of lupus-prone animals, and identify perforin-mediated cytotoxicity as a specific mechanism in the regulation of systemic autoimmunity.