MHC class I D(k) expression in hematopoietic and nonhematopoietic cells confers natural killer cell resistance to murine cytomegalovirus.
NK cell-mediated murine cytomegalovirus (MCMV) resistance (Cmv(r)) is under H-2(k) control in MA/My mice, but the underlying gene(s) is unclear. Prior genetic analysis mapped Cmv(r) to the MHC class I (MHC-I) D(k) gene interval. Because NK cell receptors are licensed by and responsive to MHC class I molecules, D(k) itself is a candidate gene. A 10-kb genomic D(k) fragment was subcloned and microinjected into MCMV-susceptible (Cmv(s)) (MA/My.L-H2(b) x C57L)F(1) or (B6 x DBA/2)F(2) embryos. Transgenic founders, which are competent for D(k) expression and germline transgene transmission, were identified and further backcrossed to MA/My.L-H2(b) or C57L mice. Remarkably, D(k) expression delivered NK-mediated resistance in either genetic background. Further, NK cells with cognate inhibitory Ly49G receptors for self-MHC-I D(k) were licensed and critical in protection against MCMV infection. In radiation bone marrow chimeras, NK resistance was significantly diminished when MHC-I D(k) expression was restricted to only hematopoietic or nonhematopoietic cells. Thus, MHC-I D(k) is the H-2(k)-linked Cmv(r) locus; these findings suggest a role for NK cell interaction with D(k)-bearing hematopoietic and nonhematopoietic cells to shape NK-mediated virus immunity.
Xie
Xuefang
X
Department of Microbiology, Division of Nephrology, and Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Stadnisky
Michael D
MD
Coats
Ebony R
ER
Ahmed Rahim
Mir Munir
MM
Lundgren
Alyssa
A
Xu
Wenhao
W
Makrigiannis
Andrew P
AP
Brown
Michael G
MG
D000818:Animals; D002678:Chimera / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D056426:Genetic Loci / Q000235:genetics*; D006413:Hematopoietic System / Q000166:cytology* / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018146:Muromegalovirus / Q000276:immunology*; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism
D016207:Cytokines; D015395:Histocompatibility Antigens Class I; C527095:Klra7 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A