http://immunol.nature.com • september 2000 • volume 1 no 3 • nature immunology Fu-D ong Shi 1, * † , H ua-Bing W ang 2, * , H ulun Li 2, * , Seokmann H ong 3 , Masaru Taniguchi 4 , H ans Link 2 , Luc Van Kaer 3 and H ans-Gustaf Ljunggren 1 Natural killer (NK) cells can affect the outcome of adaptive immune responses. NK cells, but not N K1.1 + T cells, were found to participate in the development of myasthenia gravis (a T cell–dependent, B cell– and antibody-mediated autoimmune disease) in C57BL/6 mice.The requirement for N K cells was reflected by the lack of a type 1 helper T cell response and antibodies to the acetylcholine receptor in both NK1.1 + cell–depleted and NK cell–deficient IL-18 –/– mice. T hese findings establish a previously unrecognized link between N K cells and autoreactive T and B cells. 1 M icrobiology and Tumor Biology Center, Karolinska Institutet, S-1 7 1 7 7 Stockholm, Sweden. 2 D ivision of N eurology, H uddinge U niversity H ospital, Karolinska Institutet, S-141 86 Stockholm, Sweden. 3 H oward H ughes M edical Institute, D epartment of M icrobiology and Immunology, Vanderbilt University School of M edicine, N ashville,TN 3 7 2 3 2 , USA. 4 D ivision of M olecular Immunology, Center for Biomedical Science, School of M edicine, Chiba University, 1 -8 -1 Inobana, Chuo-ku, Chiba, Japan 2 6 0 . * These authors contributed equally to this work. † Present address: Department of Immunology, IM M -23, The Scripps Research Institute, 10555 N orth Torrey Pines Road, La Jolla, CA 92037, USA. Correspondence should be addressed to H .G.L. (hans-gustaf.ljunggren@ mtc.ki.se). N atural killer cells determine the out- come of B cell–mediated autoimmunity Autoimmune diseases are inflammatory disorders, many of which have a suspected infectious etiology. Natural killer (NK) cells, as a first line of defense in combating infections, may be involved in the initiation of autoimmunity and accumulate in the target organs of cer- tain autoimmune diseases 1–3 . It has been suggested that NK or NK1.1 + T (NKT) cells serve as regulatory cells in some T cell–mediated experimental autoimmune disease, including murine models of encephalomyelitis 4,5 , colitis 6 and diabetes 7 . However, several issues regarding the role of NK cells in the development of autoimmune dis- eases remain unresolved. Few studies have been able to distinguish between effects of NK cells and effects of NKT cells, and the mechanism for the regulatory effect of NK cells in murine models remains unclear. Also still unknown is the point at which NK cells impact on the development of autoimmune disease, and the contribution of NK cells to the development of those autoimmune diseases that are primarily mediated by pathogenic antibodies. Autoantibodies produced by B cells are the primary cause of disease in a variety of autoimmune conditions, including hemolytic anemia, thyroiditis, stiff man syn- drome, pemphigus vulgaris and systemic lupus erythe- matosus 8 . Myasthenia gravis (MG) is one of the best characterized antibody-mediated autoimmune diseases because the target antigen, the nicotinic acetylcholine receptor (AChR) of neuromuscular junctions, has been well defined 9 . Experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 (B6) mice, induced by repeated immunizations with Torpedo AChR emulsified in complete Freund’s adjuvant (CFA), is a particularly useful model for identification of the pathogenic mech- anisms that cause MG in humans 10 . In both MG and EAMG, autoreactive CD4 + T cells provide help for B cells to produce antibodies to AChR 9 . Although the TH1 cytokines interferon γ (IFN-γ) and interleukin 12 (IL- 12) are critically important for the generation of EAMG in B6 mice 11,12 , the production of both T helper cell subsets 1 and 2 (TH1 and TH2) cytokines may be required for the development of full-blown EAMG 13 . To obtain a more comprehensive view of the potential role of NK and NKT cells in B cell–mediated autoimmune diseases, we examined the development of antibody-mediated EAMG in mice depleted of NK1.1 + cells, in NK cell–deficient IL-18 –/– mice, and in NKT cell–defi- cient mice. Our results demonstrate that NK cells determine the out- come of autoantibody responses to AChR via control of autoreactive T A RTICLES 245 Figure 1. Incidence and severity of EAMG in N K1.1 + cell–depleted and N KT cell–deficient mice. Mice were immunized with AChR and CFA, boosted on day 30 and 60 after immunization, and monitored for development of EAMG. (a,b) B6 mice (, n=35) treated with isotype control antibody and B6 mice depleted of N K1.1 + cells (, n=36). (c,d) W ild-type (, n=15) and J α281 –/– mice (, n=17). (e,f) W ild-type (, n=8) and CD1d1 –/– mice (, n=8). a b c d e f © 2000 Nature America Inc. • http://immunol.nature.com © 2000 Nature America Inc. • http://immunol.nature.com