NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Berzofsky, Jay A.; Terabe, Masaki

doi:10.4049/jimmunol.180.6.3627

Cited by 108 publications

(90 citation statements)

References 126 publications

(124 reference statements)

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“…Two other groups already ruled out the involvement of FBS response by measuring tumor growth in mice injected with DC exposed to mouse serum [12,15], and we likewise confirmed IFN-g secretion by NK cells in mice immunized with DC cultured in mouse serum. In immunosurveillance, some types of CD4 + cells including CD4 + CD25 + Treg cells [27,28] and type II NKT cells have suppressive effects on tumor immunity [29]. Ambrosino et al [30] were able to suppress immune surveillance with selective stimulation of CD4 + type II NKT cells, which are CD1d-dependent, but not iNKT cells.…”

Section: Discussionmentioning

confidence: 99%

DC therapy induces long‐term NK reactivity to tumors via host DC

Shimizu

Fujii

2009

Eur J Immunol

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We vaccinated mice with DC loaded with or without invariant NKT-cell ligand a-galactosylceramide and evaluated long-term resistance against tumor challenge. When mice had been given either DC or DC/galactosylceramide and were challenged with tumor cells even 6-12 months later, both NK and NKT cells were quickly activated to express CD69 and produce IFN-c. The NK cells could resist a challenge with several different tumors in vivo. The activated NK and NKT cells could be depleted with anti-NK1.1 treatment. In spite of this, the activated cells recovered, indicating that tumor-responsive NK and NKT cells were being generated continuously as a result of vaccination with DC and were not true memory cells. The NK and NKT antitumor response in DC-vaccinated mice depended on CD4 + T cells, but neither CD8 + T cells nor CD4 + CD25 + regulatory T cells. However, both vaccine DC and host DC were required for the development of long-term, tumor reactive innate immunity. These results indicate that DC therapy in mice induces long-lasting innate NK-and NKT-cell activation through a pathway that requires host DC and CD4 + T cells and that the continued generation of active NK cells resists the establishment of metastases in vivo.Key words: DC . IFN-c . NK cells . Tumor immunity . Vaccination Introduction DC are specialized APC for initiating T-cell responses. Antigenloaded DC induce antigen-specific T-cell immunity in an MHCdependent manner in murine models and humans. In addition, DC can stimulate invariant Va14 + NKT (iNKT) cells after being loaded with a-galactosylceramide (a-GalCer). Injection of a-GalCer-loaded DC (DC/Gal) leads to a more prolonged IFN-gproducing iNKT-cell response in comparison with free a-GalCer administration [1][2][3]. The IFN-g-secreting iNKT cells that develop following injection of DC/Gal are evident 2 days after immunization but dissipate 2 wk later.NK cells in the innate immune system represent a critical first line of defense against malignant transformation and infection. One way to activate NK cells involves NKT cells, which elicit cytokines from DC [2][3][4][5]. Several groups have addressed these DC-derived NK-activating cytokines, such as IL-2, IL-12, IL-15 and type I IFN. For example, Granucci et al. [6] demonstrated that TLR-ligand-activated DC, e.g. with LPS, CpG or BCG produce IL-2 in a few hours, which then activates NK cells to produce IFN-g. In addition, IL-12 is produced by iNKT-activated DC and is a primary cytokine for the production of IFN-g and cytotoxicity by NK cells [7,8]. Other cytokines such as type I IFN, IL-15 and IL-18 released during the DC-NK-cell interaction can have synergistic effects on NK function [9,10]. In particular, a membrane-bound form of DC-derived IL-15 appears to be necessary to induce proliferation in NK cells. A role for endogenous type I IFN in restricting the growth of tumors, through NK-cell activation, has also been demonstrated [11]. In this paper, we compared a-GalCer-pulsed and non-pulsed DC to induce long-term NK-and NKT-cell activation at the...

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Section: Discussionmentioning

confidence: 99%

DC therapy induces long‐term NK reactivity to tumors via host DC

Shimizu

Fujii

2009

Eur J Immunol

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“…In addition, fewer liver NKT cells were detected in IL-1␣ Ϫ/Ϫ mice than in WT mice. CD1d-restricted invariant NKT cells play a pivotal role in natural antitumor immune responses, mainly by activation of innate and adaptive immunosurveillance cells swift and potent cytokine secretion (45). Finally, in comparison to effector cells from WT mice, innate and specific antitumor effector cells from IL-1␣ Ϫ/Ϫ mice, i.e., NK cells, LAK cells, and CTL, displayed a reduced killing capacity, which correlated with reduced expression of perforin and granzyme B in purified NK cells from IL-1␣ Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 99%

Host-Derived Interleukin-1α Is Important in Determining the Immunogenicity of 3-Methylcholantrene Tumor Cells

Elkabets

Krelin

Dotan

et al. 2009

The Journal of Immunology

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Using IL-1/IL-1Ra knockout BALB/c mice, we showed that 3-methylcholatrene (3-MCA)-induced carcinogenesis is dependent on IL-1β-induced inflammatory responses. Patterns of local inflammation and tumorigenicity were similar in wild-type (WT) and IL-1α−/− mice, while in IL-1β−/− mice, tumorigenicity was attenuated and in IL-1Ra−/− mice accentuated. 3-MCA-induced fibrosarcoma cell lines from WT mice developed into progressive tumors in WT mice, while surprisingly, lines from IL-1α−/− mice formed tumors only in immunocompromized mice. 3-MCA-induced fibrosarcoma cell lines from IL-1α−/− mice, compared with lines from WT mice, manifested higher expression levels of “global” surface molecules related to Ag presentation and interactions with immune surveillance cells (MHC class I, B7.1, B7.2, L-selectin, and NKG2D ligands) and were eradicated mainly by CD4+- and CD8+-dependent T cell responses. Concomitantly, at the injection site of 3-MCA-induced fibrosarcoma cells derived from IL-1α−/− mice, a leukocyte infiltrate, subsequently replaced by a scar-like tissue, was observed. Immune aberrations in NK cell maturation, antitumor specific immunity and killing capacity of effector cells were observed in IL-1α−/− mice, in contrast to WT mice. Thus, we demonstrate in this study the significance of host-derived IL-1α in cancer immunoediting, by affecting innate and specific immunosurveillance mechanisms. Overall, the results presented in this study, together with our previous studies, attest to differential involvement of IL-1α and IL-1β in tumorigenesis; host-derived IL-1β mainly controls inflammation, while concomitantly, IL-1α controls immunosurveillance of the arising malignant cells. Elucidation of the involvement of the IL-1 molecules in the malignant process will hopefully lead to the development of novel approaches for chemoprevention and immunotherapy.

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“…CD1d prevents the activation of both iNKT and variant NKT cells that exert opposing functions, 57,58 and this may complicate the interpretation of the results obtained by Rhee et al In a subsequent study, Ragin et al 59 found a trend for protection from lethal toxic shock in Balb/ c.CD1d À/À and Balb/c.Ja18 À/À mice receiving D-galactosamine and SEB in comparison with wild-type Balb/c mice challenged with the same agents. Although reporting both interesting and important results, these studies did not address the direct effect of SAgs on iNKT cells or on human iNKT cell responses.…”

Section: Human Inkt Cells Are Activated By Bacterial Sagsmentioning

confidence: 99%

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

et al. 2011

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Invariant NKT (iNKT) cells are infrequent but important immunomodulatory lymphocytes that exhibit CD1d-restricted reactivity with glycolipid Ags. iNKT cells express a unique T-cell receptor (TCR) composed of an invariant a-chain, paired with a limited range of b-chains. Superantigens (SAgs) are microbial toxins defined by their ability to activate conventional T cells in a TCR b-chain variable domain (Vb)-specific manner. However, whether iNKT cells are directly activated by bacterial SAgs remains an open question. Herein, we explored the responsiveness of mouse and human iNKT cells to a panel of staphylococcal and streptococcal SAgs and examined the contribution of major histocompatibility complex (MHC) class II and CD1d to these responses. Bacterial SAgs that target mouse Vb8, such as staphylococcal enterotoxin B (SEB), were able to activate mouse hybridoma and primary hepatic iNKT cells in the presence of mouse APCs expressing human leukocyte antigen (HLA)-DR4. iNKT cell-mediated cytokine secretion in SEB-challenged HLA-DR4-transgenic mice was CD1d-independent and accompanied by a high interferon-c:interleukin-4 ratio consistent with an in vivo Th1 bias. Furthermore, iNKT cells from SEB-injected HLA-DR4-transgenic mice, and iNKT cells from SEB-treated human PBMCs, showed early activation by intracellular cytokine staining and CD69 expression. Unlike iNKT cell stimulation by a-galactosylceramide, stimulation by SEB did not induce TCR downregulation of either mouse or human iNKT cells. We conclude that Vb8-targeting bacterial SAgs can activate iNKT cells by utilizing a novel pathway that requires MHC class II interactions, but not CD1d. Therefore, iNKT cells fulfill important effector functions in response to bacterial SAgs and may provide attractive targets in the management of SAg-induced illnesses.

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NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

Cited by 108 publications

References 126 publications

DC therapy induces long‐term NK reactivity to tumors via host DC

DC therapy induces long‐term NK reactivity to tumors via host DC

Host-Derived Interleukin-1α Is Important in Determining the Immunogenicity of 3-Methylcholantrene Tumor Cells

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

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