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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 anti-NK1.1 mAb on MOG35-55 induced EAE in β2m−/− mice. The mice were immunized two times with MOG35-55 peptide for  EAE induction. On the day before first immunization, control mAb (A) or anti-NK1.1 mAb (B) was intravenously injected. This is a representative of  three experiments with similar results.
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Figure 3: Effect of anti-NK1.1 mAb on MOG35-55 induced EAE in β2m−/− mice. The mice were immunized two times with MOG35-55 peptide for EAE induction. On the day before first immunization, control mAb (A) or anti-NK1.1 mAb (B) was intravenously injected. This is a representative of three experiments with similar results.

Mentions: Injection of anti-NK1.1 mAb deletes both NK and NK–T cells. Since our primary target was NK cells, experimental systems were required in which involvement of NK–T cells can be entirely excluded. Because NK–T cells, positively selected against the CD1 molecule, are absent in β2m−/− mice defective for expression of CD1 (32, 33), we used this mutant strain for further analysis. Previous studies showed that β2m−/− mice are susceptible to some, but not all autoimmune diseases (34–36). We first examined whether immunization with MOG35-55 can induce EAE in this mutant. As shown in Fig. 3 A and Table 1, the mutant mice developed monophasic EAE, of which clinical course is comparable to that induced in wild-type B6 mice except for significantly later onset of illness (P <0.001). To our knowledge, this is the first experimental proof using knockout mice that shows that even when class I–restricted cells including CD8+ T cells, CD4−CD8− T cells, and NK–T cells are virtually absent, there is no alteration in EAE induction, spontaneous recovery, or resistance against relapses. Although a previous report has documented that there is a higher frequency of EAE relapses in CD8−/− mice (6), we have not seen any relapse in the mice lacking CD8+ T cells.


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 anti-NK1.1 mAb on MOG35-55 induced EAE in β2m−/− mice. The mice were immunized two times with MOG35-55 peptide for  EAE induction. On the day before first immunization, control mAb (A) or anti-NK1.1 mAb (B) was intravenously injected. This is a representative of  three experiments with similar results.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199138&req=5

Figure 3: Effect of anti-NK1.1 mAb on MOG35-55 induced EAE in β2m−/− mice. The mice were immunized two times with MOG35-55 peptide for EAE induction. On the day before first immunization, control mAb (A) or anti-NK1.1 mAb (B) was intravenously injected. This is a representative of three experiments with similar results.
Mentions: Injection of anti-NK1.1 mAb deletes both NK and NK–T cells. Since our primary target was NK cells, experimental systems were required in which involvement of NK–T cells can be entirely excluded. Because NK–T cells, positively selected against the CD1 molecule, are absent in β2m−/− mice defective for expression of CD1 (32, 33), we used this mutant strain for further analysis. Previous studies showed that β2m−/− mice are susceptible to some, but not all autoimmune diseases (34–36). We first examined whether immunization with MOG35-55 can induce EAE in this mutant. As shown in Fig. 3 A and Table 1, the mutant mice developed monophasic EAE, of which clinical course is comparable to that induced in wild-type B6 mice except for significantly later onset of illness (P <0.001). To our knowledge, this is the first experimental proof using knockout mice that shows that even when class I–restricted cells including CD8+ T cells, CD4−CD8− T cells, and NK–T cells are virtually absent, there is no alteration in EAE induction, spontaneous recovery, or resistance against relapses. Although a previous report has documented that there is a higher frequency of EAE relapses in CD8−/− mice (6), we have not seen any relapse in the mice lacking CD8+ T cells.

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