Natural killers have memory, too

New findings overturn longstanding dogma, could shed light on mysteries in immunity

By | April 17, 2006

Natural killer (NK) cells can mount hypersensitive immune responses against specific antigens they have encountered before, the hallmark of adaptive immunity, scientists report in the May issue of Nature Immunology. These unexpected findings may overturn the longstanding dogma that adaptive immunity is limited to only T cells and B cells in higher vertebrates, according to study author Ulrich von Andrian at Harvard Medical School in Boston. "It's like Christopher Columbus bumping into a new continent," Philip Askenase at Yale University in New Haven, Conn., who did not participate in this study, told The Scientist. During the study, von Andrian and his colleagues examined how mice responded to haptens, compounds that elicit immune responses when bound to carrier molecules such as proteins. Surprisingly, they discovered the bladders and skin of Rag2-deficient mice, which lack T and B cells, became inflamed -- indicating an immune response -- after recurring exposure to hapten 2,4-dinitrofluorobenzene (DNFB), showing a similar response to wild-type mice. In an additional experiment with a chemically distinct hapten, oxazolone, Rag2-deficient mice responded only to haptens to which they were previously exposed. Moreover, Rag2-deficient mice sensitized against DNFB still responded to the hapten even four weeks later, a sign of persistent immunological memory. Immunofluorescence staining of DNFB-sensitized mice ears showed hapten exposure led to substantial accumulation of NK cells in the inflamed tissue of both Rag2-deficient and wild-type mice. Rag2-deficient mice given antibodies targeting NK cells stopped responding to repeated DNFB exposures. When the researchers transferred NK cells from DNFB-sensitized mice into non-sensitized Rag2-deficient mice, the recipients displayed hypersensitivity against the hapten. Transferring other leukocytes, however, did not produce hypersensitivity, demonstrating only NK cells are required for this adaptive immune response. Mammalian NK cells consist of many subsets with different compositions of receptors. When they compared NK cells from DNFB-sensitized mice, the researchers found that liver -- but not spleen -- NK cells induced hypersensitivity in non-sensitized mice. To find out how NK cells detect and respond to haptens, von Andrian and his colleagues examined NK cell receptor NKG2D, which activates NK cells after detecting stress markers on other cells. When they gave antibodies targeting NKG2D to hapten-sensitized Rag2-deficient mice, the antibodies appear to suppress hypersensitivity toward hapten doses. However, since adaptive memory is so far seen in only liver NK cells and NKG2D is expressed on nearly all NK cells, the researchers feel it unlikely the receptor is directly responsible for hapten recognition. Instead, they suggest it may serve a role much like that of costimulatory molecules on T cells. Von Andrian should be "admired for recognizing this new phenomenon, which was totally unexpected," Martin Flajnik at the University of Maryland in Baltimore, who did not participate in this study, told The Scientist. "I plan to re-investigate findings we couldn't explain in light of this work," Askenase said. Future studies should investigate which molecular mechanisms NK cells use to distinguish between different haptens without the aid of the millions of proteins generated in T and B cells via the recombination-activating genes, von Andrian told The Scientist. The diversity in NK cells' receptor compositions could be the root of their adaptive immunity, but the researcher could not rule out the possibility that NK cells possess a means of generating diverse immune receptors -- a technique employed by lampreys and perhaps insects. Additional experiments should also investigate whether NK cells exhibit adaptive immunity in tissues other than spleen and liver, as well as whether conventional antigens can also trigger memory NK cells. "If this does extend to other antigens, this could reflect on autoimmunity, infectious immunity, cancer immunity, transplantation immunity," Askenase said. Charles Q. Choi Links within this article Tudor Toma. "Can NK cells maintain the remission of MS?" The Scientist, March 16, 2001. J.P. Roberts. "T-cell subsets: On the immunity warpath." The Scientist, May 5, 2003. J.G. O'Leary et al. "T cell- and B cell-independent adaptive immunity mediated by natural killer cells." Nature Immunology, May 2006. M.M. Davis. "Panning for T-cell gold." The Scientist, July 19, 2004. Tudor Toma. "Early determination of B cell fate." The Scientist, May 22, 2002. Ulrich von Andrian Philip Askenase Charles Choi. "Fetal proteins protect against rejection." The Scientist, March 17, 2006. Martin Flajnik J.P. Roberts. "AID and its impact on antibody genetic alteration." The Scientist, March 10, 2003. Cathy Holding. "Evolution of innate immunity." The Scientist, July 8, 2004. C.Q. Choi. "Insects may have complex immunity." The Scientist, August 19, 2005.

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