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

Michael D. Bern, Diana L. Beckman, Takashi Ebihara, Samantha M. Taffner, Jennifer Poursine-Laurent, J. Michael White, Wayne M. Yokoyama

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)E8440-E8447
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number40
DOIs
StatePublished - Oct 3 2017

Keywords

  • Immunity
  • Lymphocytes
  • MHC class I
  • NK cells
  • Tolerance

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