Limits...
Differential tumor surveillance by natural killer (NK) and NKT cells.

Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI - J. Exp. Med. (2000)

Bottom Line: Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis.A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity.This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide.

View Article: PubMed Central - PubMed

Affiliation: Cellular Cytotoxicity Laboratory, Austin Research Institute, Austin and Repatriation Medical Centre, Heidelberg, 3084 Victoria, Australia. m.smyth@ari.unimelb.edu.au

ABSTRACT
Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12 does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis. In the models examined, CD3(-) NK cells were responsible for tumor rejection and protection from metastasis in models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12. A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity. In particular, T cell receptor Jalpha281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide.

Show MeSH

Related in: MedlinePlus

NKT cells directly lyse MCA-induced sarcoma. Thymus and liver NKT cells (NK1.1+TCR-β+) were sorted from B6 and B6.P−/− mice, and were examined in (A) 4-h and (B) 18-h 51Cr-release assays for direct lysis of a panel of labeled target cells as indicated. Some effector cells were cultured in IL-2 (50 U/ml) and IL-12 (20 pg/ml) throughout the course of the assay (+ IL-2/12). NKT effectors were tested at four different E/T ratios (20, 5, 1, 0.5), with an E/T ratio of 20:1 shown. In A, sorted liver NKT cells are compared with sorted liver NK cells. In B, sorted thymus NKT cells are with sorted thymus T cells (CD4+CD8− HSA−). The data is recorded as the mean ± SEM, the spontaneous release of 51Cr was always <15% (subtracted from all tests), and each test was performed using duplicate samples. NT, not tested.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2195840&req=5

Figure 4: NKT cells directly lyse MCA-induced sarcoma. Thymus and liver NKT cells (NK1.1+TCR-β+) were sorted from B6 and B6.P−/− mice, and were examined in (A) 4-h and (B) 18-h 51Cr-release assays for direct lysis of a panel of labeled target cells as indicated. Some effector cells were cultured in IL-2 (50 U/ml) and IL-12 (20 pg/ml) throughout the course of the assay (+ IL-2/12). NKT effectors were tested at four different E/T ratios (20, 5, 1, 0.5), with an E/T ratio of 20:1 shown. In A, sorted liver NKT cells are compared with sorted liver NK cells. In B, sorted thymus NKT cells are with sorted thymus T cells (CD4+CD8− HSA−). The data is recorded as the mean ± SEM, the spontaneous release of 51Cr was always <15% (subtracted from all tests), and each test was performed using duplicate samples. NT, not tested.

Mentions: To test the possibility that MCA-induced sarcomas were sensitive to direct lysis by NKT cells, we determined the basal and activated cytotoxicity of NKT cells against MCA-1 (a sarcoma derived from B6.Jα281−/− mice) and other tumor target cell lines (Fig. 4). Sorted NKT cells from the liver of B6 mice displayed significant lysis of MCA-1 in a 4-h assay, particularly with IL-2/IL-12 stimulation (Fig. 4 A). The lytic activity of sorted resting liver NK cells was higher than resting NKT cells against all the tumor target cells, with RM-1 tumor cells comparatively insensitive to both NK and NKT cells. Thymus NKT cells demonstrated lower levels of lysis of MCA-1 than liver NKT cells, but they too demonstrated enhanced lysis with IL-2/IL-12 stimulation. Although resting NKT cells did not display significantly greater lysis of target cells in 18-h assays, both thymus and liver NKT cells stimulated in IL-2/IL-12 over the assay period were considerably more lytic than in the 4-h assay (Fig. 4 B). By contrast, NKT cells sorted from the thymi of B6.P−/− mice were unable to lyse MCA-1, even after IL-2/IL-12 stimulation for 18 h, suggesting that NKT cell lysis of MCA-1 was strictly perforin dependent (Fig. 4 B). Control thymus T cells did not display lytic activity in the absence or presence of IL-2/IL-12 against YAC-1 or MCA-1.


Differential tumor surveillance by natural killer (NK) and NKT cells.

Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI - J. Exp. Med. (2000)

NKT cells directly lyse MCA-induced sarcoma. Thymus and liver NKT cells (NK1.1+TCR-β+) were sorted from B6 and B6.P−/− mice, and were examined in (A) 4-h and (B) 18-h 51Cr-release assays for direct lysis of a panel of labeled target cells as indicated. Some effector cells were cultured in IL-2 (50 U/ml) and IL-12 (20 pg/ml) throughout the course of the assay (+ IL-2/12). NKT effectors were tested at four different E/T ratios (20, 5, 1, 0.5), with an E/T ratio of 20:1 shown. In A, sorted liver NKT cells are compared with sorted liver NK cells. In B, sorted thymus NKT cells are with sorted thymus T cells (CD4+CD8− HSA−). The data is recorded as the mean ± SEM, the spontaneous release of 51Cr was always <15% (subtracted from all tests), and each test was performed using duplicate samples. NT, not tested.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195840&req=5

Figure 4: NKT cells directly lyse MCA-induced sarcoma. Thymus and liver NKT cells (NK1.1+TCR-β+) were sorted from B6 and B6.P−/− mice, and were examined in (A) 4-h and (B) 18-h 51Cr-release assays for direct lysis of a panel of labeled target cells as indicated. Some effector cells were cultured in IL-2 (50 U/ml) and IL-12 (20 pg/ml) throughout the course of the assay (+ IL-2/12). NKT effectors were tested at four different E/T ratios (20, 5, 1, 0.5), with an E/T ratio of 20:1 shown. In A, sorted liver NKT cells are compared with sorted liver NK cells. In B, sorted thymus NKT cells are with sorted thymus T cells (CD4+CD8− HSA−). The data is recorded as the mean ± SEM, the spontaneous release of 51Cr was always <15% (subtracted from all tests), and each test was performed using duplicate samples. NT, not tested.
Mentions: To test the possibility that MCA-induced sarcomas were sensitive to direct lysis by NKT cells, we determined the basal and activated cytotoxicity of NKT cells against MCA-1 (a sarcoma derived from B6.Jα281−/− mice) and other tumor target cell lines (Fig. 4). Sorted NKT cells from the liver of B6 mice displayed significant lysis of MCA-1 in a 4-h assay, particularly with IL-2/IL-12 stimulation (Fig. 4 A). The lytic activity of sorted resting liver NK cells was higher than resting NKT cells against all the tumor target cells, with RM-1 tumor cells comparatively insensitive to both NK and NKT cells. Thymus NKT cells demonstrated lower levels of lysis of MCA-1 than liver NKT cells, but they too demonstrated enhanced lysis with IL-2/IL-12 stimulation. Although resting NKT cells did not display significantly greater lysis of target cells in 18-h assays, both thymus and liver NKT cells stimulated in IL-2/IL-12 over the assay period were considerably more lytic than in the 4-h assay (Fig. 4 B). By contrast, NKT cells sorted from the thymi of B6.P−/− mice were unable to lyse MCA-1, even after IL-2/IL-12 stimulation for 18 h, suggesting that NKT cell lysis of MCA-1 was strictly perforin dependent (Fig. 4 B). Control thymus T cells did not display lytic activity in the absence or presence of IL-2/IL-12 against YAC-1 or MCA-1.

Bottom Line: Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis.A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity.This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide.

View Article: PubMed Central - PubMed

Affiliation: Cellular Cytotoxicity Laboratory, Austin Research Institute, Austin and Repatriation Medical Centre, Heidelberg, 3084 Victoria, Australia. m.smyth@ari.unimelb.edu.au

ABSTRACT
Natural tumor surveillance capabilities of the host were investigated in six different mouse tumor models where endogenous interleukin (IL)-12 does or does not dictate the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to establish the relative importance of natural killer (NK) and NK1.1(+) T (NKT) cells in protection from tumor initiation and metastasis. In the models examined, CD3(-) NK cells were responsible for tumor rejection and protection from metastasis in models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12. A protective role for NKT cells was only observed when tumor rejection required endogenous IL-12 activity. In particular, T cell receptor Jalpha281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenously administered potent stimulators such as IL-12 or alpha-galactosylceramide.

Show MeSH
Related in: MedlinePlus