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Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells.

Zhang B, Yamamura T, Kondo T, Fujiwara M, Tabira T - J. Exp. Med. (1997)

Bottom Line: The disease enhancement was associated with augmentation of T cell proliferation and production of Th1 cytokines in response to MOG35-55.We further showed that NK cells inhibit T cell proliferation triggered by antigen or cytokine stimulation.Taken together, we conclude that NK cells are an important regulator for EAE in both induction and effector phases.

View Article: PubMed Central - PubMed

Affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience, Tokyo, Japan.

ABSTRACT
In this report, we establish a regulatory role of natural killer (NK) cells in experimental autoimmune encephalomyelitis (EAE), a prototype T helper cell type 1 (Th1)-mediated disease. Active sensitization of C57BL/6 (B6) mice with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide induces a mild form of monophasic EAE. When mice were deprived of NK cells by antibody treatment before immunization, they developed a more serious form of EAE associated with relapse. Aggravation of EAE by NK cell deletion was also seen in beta 2-microglobulin-/- (beta 2m-/-) mice, indicating that NK cells can play a regulatory role in a manner independent of CD8+ T cells or NK1.1+ T cells (NK-T cells). The disease enhancement was associated with augmentation of T cell proliferation and production of Th1 cytokines in response to MOG35-55. EAE passively induced by the MOG35-55-specific T cell line was also enhanced by NK cell deletion in B6, beta 2m-/-, and recombination activation gene 2 (RAG-2)-/- mice, indicating that the regulation by NK cells can be independent of T, B, or NK-T cells. We further showed that NK cells inhibit T cell proliferation triggered by antigen or cytokine stimulation. Taken together, we conclude that NK cells are an important regulator for EAE in both induction and effector phases.

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Effect of NK cell deletion on T cell response to MOG35-55.  (A) LN cell proliferative response. 11 d after immunization with MOG35-55,  draining LN cells were prepared and their proliferative responses to  MOG35-55, PLP136-150 (PLP), and rat myelin basic protein89-101 (MBP) (reference 9) were assayed by a standard method. 1 d before immunization,  mice were injected intravenously either with control mAb or with anti-NK1.1 mAb. Data represent mean ± SD of the mean cpm obtained by  triplicate cultures in four independent experiments. Each column shows  the data of wild-type B6 mice pretreated with control M-11 mAb  (B6,control), B6 pretreated with anti-NK1.1 mAb (B6,anti-NK1.1),  β2m−/− mice pretreated with control M-11 mAb (b2m−/−, control), and  β2m−/− mice pretreated with anti-NK1.1 mAb (b2m−/−, anti-NK1.1).  (B) IFN-γ production by LN cells. 11 d after immunization with  MOG35-55, the LN cells from control mAb– (control) or anti-NK1.1 mAb– treated (anti-NK1.1) B6 or β2m−/− mice were cultured for 40 h with  (MOG+) or without MOG35-55 (MOG−) and the supernatants were collected for measurement of IFN-γ, IL-2, IL-4, and IL-10 by ELISA. Although IL-2, IL-4, and IL-10 were not detectable in this experimental  setting, significant production of IFM-γ was measured as shown here.  Data represent mean ± SD of the mean value obtained by duplicate assays  in four independent experiments.
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Figure 5: Effect of NK cell deletion on T cell response to MOG35-55. (A) LN cell proliferative response. 11 d after immunization with MOG35-55, draining LN cells were prepared and their proliferative responses to MOG35-55, PLP136-150 (PLP), and rat myelin basic protein89-101 (MBP) (reference 9) were assayed by a standard method. 1 d before immunization, mice were injected intravenously either with control mAb or with anti-NK1.1 mAb. Data represent mean ± SD of the mean cpm obtained by triplicate cultures in four independent experiments. Each column shows the data of wild-type B6 mice pretreated with control M-11 mAb (B6,control), B6 pretreated with anti-NK1.1 mAb (B6,anti-NK1.1), β2m−/− mice pretreated with control M-11 mAb (b2m−/−, control), and β2m−/− mice pretreated with anti-NK1.1 mAb (b2m−/−, anti-NK1.1). (B) IFN-γ production by LN cells. 11 d after immunization with MOG35-55, the LN cells from control mAb– (control) or anti-NK1.1 mAb– treated (anti-NK1.1) B6 or β2m−/− mice were cultured for 40 h with (MOG+) or without MOG35-55 (MOG−) and the supernatants were collected for measurement of IFN-γ, IL-2, IL-4, and IL-10 by ELISA. Although IL-2, IL-4, and IL-10 were not detectable in this experimental setting, significant production of IFM-γ was measured as shown here. Data represent mean ± SD of the mean value obtained by duplicate assays in four independent experiments.

Mentions: To know the immunological basis for the enhancement of EAE by NK cell deletion, we measured the proliferation of LN cells and their Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-10) cytokine production in response to the MOG peptide. As shown in Fig. 5 A, the proliferative response to MOG35-55 was significantly enhanced with anti-NK1.1 mAb treatment in both wild-type and βm−/− mice. Production of IFN-γ by the LN cells was also enhanced by NK deletion in vivo (Fig. 5 B). We also measured the cytokine levels in the sera on day 12 after first immunization. As shown in Table 2, the levels of IFN-γ and TNF-α in the sera were dramatically elevated in NK cell–deleted mice compared with controls in both wild-type and β2m−/− mice. It was interesting to note that the cytokine levels roughly correlated with clinical severity of EAE induced in each group of mice. In contrast, the level of IL-4 was not altered by NK cell deletion. The association of EAE enhancement with enhanced production of Th1 cytokines implied that NK cell deletion leads to the augmentation of MOG35-55–specific Th1 induction, whereas Th2 induction is unaltered or relatively inhibited.


Regulation of experimental autoimmune encephalomyelitis by natural killer (NK) cells.

Zhang B, Yamamura T, Kondo T, Fujiwara M, Tabira T - J. Exp. Med. (1997)

Effect of NK cell deletion on T cell response to MOG35-55.  (A) LN cell proliferative response. 11 d after immunization with MOG35-55,  draining LN cells were prepared and their proliferative responses to  MOG35-55, PLP136-150 (PLP), and rat myelin basic protein89-101 (MBP) (reference 9) were assayed by a standard method. 1 d before immunization,  mice were injected intravenously either with control mAb or with anti-NK1.1 mAb. Data represent mean ± SD of the mean cpm obtained by  triplicate cultures in four independent experiments. Each column shows  the data of wild-type B6 mice pretreated with control M-11 mAb  (B6,control), B6 pretreated with anti-NK1.1 mAb (B6,anti-NK1.1),  β2m−/− mice pretreated with control M-11 mAb (b2m−/−, control), and  β2m−/− mice pretreated with anti-NK1.1 mAb (b2m−/−, anti-NK1.1).  (B) IFN-γ production by LN cells. 11 d after immunization with  MOG35-55, the LN cells from control mAb– (control) or anti-NK1.1 mAb– treated (anti-NK1.1) B6 or β2m−/− mice were cultured for 40 h with  (MOG+) or without MOG35-55 (MOG−) and the supernatants were collected for measurement of IFN-γ, IL-2, IL-4, and IL-10 by ELISA. Although IL-2, IL-4, and IL-10 were not detectable in this experimental  setting, significant production of IFM-γ was measured as shown here.  Data represent mean ± SD of the mean value obtained by duplicate assays  in four independent experiments.
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Related In: Results  -  Collection

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Figure 5: Effect of NK cell deletion on T cell response to MOG35-55. (A) LN cell proliferative response. 11 d after immunization with MOG35-55, draining LN cells were prepared and their proliferative responses to MOG35-55, PLP136-150 (PLP), and rat myelin basic protein89-101 (MBP) (reference 9) were assayed by a standard method. 1 d before immunization, mice were injected intravenously either with control mAb or with anti-NK1.1 mAb. Data represent mean ± SD of the mean cpm obtained by triplicate cultures in four independent experiments. Each column shows the data of wild-type B6 mice pretreated with control M-11 mAb (B6,control), B6 pretreated with anti-NK1.1 mAb (B6,anti-NK1.1), β2m−/− mice pretreated with control M-11 mAb (b2m−/−, control), and β2m−/− mice pretreated with anti-NK1.1 mAb (b2m−/−, anti-NK1.1). (B) IFN-γ production by LN cells. 11 d after immunization with MOG35-55, the LN cells from control mAb– (control) or anti-NK1.1 mAb– treated (anti-NK1.1) B6 or β2m−/− mice were cultured for 40 h with (MOG+) or without MOG35-55 (MOG−) and the supernatants were collected for measurement of IFN-γ, IL-2, IL-4, and IL-10 by ELISA. Although IL-2, IL-4, and IL-10 were not detectable in this experimental setting, significant production of IFM-γ was measured as shown here. Data represent mean ± SD of the mean value obtained by duplicate assays in four independent experiments.
Mentions: To know the immunological basis for the enhancement of EAE by NK cell deletion, we measured the proliferation of LN cells and their Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-10) cytokine production in response to the MOG peptide. As shown in Fig. 5 A, the proliferative response to MOG35-55 was significantly enhanced with anti-NK1.1 mAb treatment in both wild-type and βm−/− mice. Production of IFN-γ by the LN cells was also enhanced by NK deletion in vivo (Fig. 5 B). We also measured the cytokine levels in the sera on day 12 after first immunization. As shown in Table 2, the levels of IFN-γ and TNF-α in the sera were dramatically elevated in NK cell–deleted mice compared with controls in both wild-type and β2m−/− mice. It was interesting to note that the cytokine levels roughly correlated with clinical severity of EAE induced in each group of mice. In contrast, the level of IL-4 was not altered by NK cell deletion. The association of EAE enhancement with enhanced production of Th1 cytokines implied that NK cell deletion leads to the augmentation of MOG35-55–specific Th1 induction, whereas Th2 induction is unaltered or relatively inhibited.

Bottom Line: The disease enhancement was associated with augmentation of T cell proliferation and production of Th1 cytokines in response to MOG35-55.We further showed that NK cells inhibit T cell proliferation triggered by antigen or cytokine stimulation.Taken together, we conclude that NK cells are an important regulator for EAE in both induction and effector phases.

View Article: PubMed Central - PubMed

Affiliation: Department of Demyelinating Disease and Aging, National Institute of Neuroscience, Tokyo, Japan.

ABSTRACT
In this report, we establish a regulatory role of natural killer (NK) cells in experimental autoimmune encephalomyelitis (EAE), a prototype T helper cell type 1 (Th1)-mediated disease. Active sensitization of C57BL/6 (B6) mice with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide induces a mild form of monophasic EAE. When mice were deprived of NK cells by antibody treatment before immunization, they developed a more serious form of EAE associated with relapse. Aggravation of EAE by NK cell deletion was also seen in beta 2-microglobulin-/- (beta 2m-/-) mice, indicating that NK cells can play a regulatory role in a manner independent of CD8+ T cells or NK1.1+ T cells (NK-T cells). The disease enhancement was associated with augmentation of T cell proliferation and production of Th1 cytokines in response to MOG35-55. EAE passively induced by the MOG35-55-specific T cell line was also enhanced by NK cell deletion in B6, beta 2m-/-, and recombination activation gene 2 (RAG-2)-/- mice, indicating that the regulation by NK cells can be independent of T, B, or NK-T cells. We further showed that NK cells inhibit T cell proliferation triggered by antigen or cytokine stimulation. Taken together, we conclude that NK cells are an important regulator for EAE in both induction and effector phases.

Show MeSH
Related in: MedlinePlus