title: Ly49C Impairs NK Cell Memory in Mouse Cytomegalovirus Infection.
abstract: NK cells possess inhibitory receptors that are responsible for self-MHC class I recognition; beyond their inhibitory function, accumulating evidence indicates that such receptors confer NK cell functional competence through an unclear process termed "licensing." Ly49C is the main self-specific inhibitory Ly49 receptor in H-2(b) C57BL/6 (B6) mice. We used B6 Ly49C-transgenic and B6 β2 microglobulin (β2m)-knockout Ly49C-transgenic mice to investigate the impact of licensing through this inhibitory receptor in precursor and mature NK cells. We found that self-specific inhibitory receptors affected NK cell precursor survival and proliferation at particular developmental stages in an MHC class I-dependent manner. The presence of Ly49C impacted the NK cell repertoire in a β2m-dependent manner, with reduced Ly49A(+), Ly49G2(+), and Ly49D(+) subsets, an increased DNAM-1(+) subset, and higher NKG2D expression. Licensed NK cells displayed a skewed distribution of the maturation stages, which was characterized by differential CD27 and CD11b expression, toward the mature phenotypes. We found that Ly49C-mediated licensing induced a split effect on NK cell functions, with increased cytokine-production capabilities following engagement of various activating receptors while cytotoxicity remained unchanged. Analysis of licensed NK cell functions in vivo, in a system of mouse CMV infection, indicated that licensing did not play a major role in the NK cell antiviral response during acute infection, but it strongly impaired the generation and/or persistence of memory NK cells. This study unravels multifaceted effects of licensing on NK cell populations and their functions.
authors.affiliation: Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia 6009, Australia; and.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Forbes
authors.affiliation: Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia 6009, Australia; and.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Scalzo
authors.affiliation: Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia 6009, Australia; and Centre for Ophthalmology and Vision Science, University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia 6009, Australia; and Centre for Ophthalmology and Vision Science, University of Western Australia, Crawley, Western Australia 6009, Australia jerome@lei.org.au.
authors.forename: Jerome D
authors.identifier: 0000-0001-6081-8494
authors.initials: JD
authors.lastname: Coudert
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D006566:Herpesviridae Infections / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007113:Immunity, Innate; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000276:immunology*; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000235:genetics / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D015395:Histocompatibility Antigens Class I; C527086:Klrk1 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K