Immunoreceptor tyrosine-based inhibitory motif-dependent functions of an MHC class I-specific NK cell receptor.

Autor:	Bern MD; Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.; Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110., Beckman DL; Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110., Ebihara T; Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110., Taffner SM; Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110., Poursine-Laurent J; Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110., White JM; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110., Yokoyama WM; Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; yokoyama@dom.wustl.edu.; Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Oct 03; Vol. 114 (40), pp. E8440-E8447. Date of Electronic Publication: 2017 Sep 18.
DOI:	10.1073/pnas.1713064114
Abstrakt:	Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self-MHC-I. Self-MHC-I also "licenses" NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development. Competing Interests: Conflict of interest statement: Reviewer W.E.S. was previously a paid advisor for an NIH Core Center grant to Washington University, headed by W.M.Y. Neither W.E.S. nor W.M.Y. are active collaborators.
Databáze:	MEDLINE
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