Continuous engagement of a self-specific activation receptor induces NK cell tolerance

Sandeep K. Tripathy, Peter A. Keyel, Liping Yang, Jeanette T. Pingel, Tammy P. Cheng, Achim Schneeberger, Wayne M. Yokoyama

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

Natural killer (NK) cell tolerance mechanisms are incompletely understood. One possibility is that they possess self-specific activation receptors that result in hyporesponsiveness unless modulated by self-major histocompatability complex (MHC)-specific inhibitory receptors. As putative self-specific activation receptors have not been well characterized, we studied a transgenic C57BL/6 mouse that ubiquitously expresses m157 (m157-Tg), which is the murine cytomegalovirus (MCMV)-encoded ligand for the Ly49H NK cell activation receptor. The transgenic mice were more susceptible to MCMV infection and were unable to reject m157-Tg bone marrow, suggesting defects in Ly49H+ NK cells. There was a reversible hyporesponsiveness of Ly49H+ NK cells that extended to Ly49H-independent stimuli. Continuous Ly49H-m157 interaction was necessary for the functional defects. Interestingly, functional defects occurred when mature wild-type NK cells were adoptively transferred to m157-Tg mice, suggesting that mature NK cells may acquire hyporesponsiveness. Importantly, NK cell tolerance caused by Ly49H-m157 interaction was similar in NK cells regardless of expression of Ly49C, an inhibitory receptor specific for a self-MHC allele in C57BL/6 mice. Thus, engagement of self-specific activation receptors in vivo induces an NK cell tolerance effect that is not affected by self-MHC-specific inhibitory receptors.

Original languageEnglish
Pages (from-to)1829-1841
Number of pages13
JournalJournal of Experimental Medicine
Volume205
Issue number8
DOIs
StatePublished - Aug 4 2008

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    Tripathy, S. K., Keyel, P. A., Yang, L., Pingel, J. T., Cheng, T. P., Schneeberger, A., & Yokoyama, W. M. (2008). Continuous engagement of a self-specific activation receptor induces NK cell tolerance. Journal of Experimental Medicine, 205(8), 1829-1841. https://doi.org/10.1084/jem.20072446