TY - JOUR
T1 - Molecular genetic characterization of the distal NKC recombination hotspot and putative murine CMV resistance control locus
AU - Scalzo, Anthony A.
AU - Wheat, Roy
AU - Dubbelde, Chad
AU - Stone, Laurie
AU - Clark, Patricia
AU - Du, Ying
AU - Dong, Naomi
AU - Stoll, Janis
AU - Yokoyama, Wayne M.
AU - Brown, Michael G.
N1 - Funding Information:
Acknowledgements We thank Kim Marlotte and Lolita Bland for animal care and breeding. This work was supported by NIH grants to M.G.B. (AI50072) and to W.M.Y. who is an investigator of the Howard Hughes Medical Institute. M.G.B. also received support from the Department of Internal Medicine and the Beirne Carter Center, University of Virginia. A.A.S. is supported by grants 990646 and 139178 from the National Health and Medical Research Council of Australia.
PY - 2003/9/1
Y1 - 2003/9/1
N2 - The NK gene complex (NKC) controls murine cytomegalovirus (MCMV) immunity through Cmv1-dependent natural killer (NK) cell responses. Ly49H expression correlates with Cmv1 phenotypes in different inbred strains, is required for MCMV resistance in C57BL/6 (B6) mice, and its interaction with the MCMV encoded m157 protein leads to NK cell-mediated destruction of virus-infected cells. However, genetic mapping studies have previously indicated that Cmv1 should reside in the D6Wum9-16 NKC interval, distal to Ly49h. Since these data suggested that multiple NKC-linked loci could regulate viral immunity, a putative MCMV resistance control (Mrc) locus was pinpointed to within the D6Wum9-16 interval on a NKC-aligned bacterial artificial chromosome (BAC). Sequence analysis of BAC 151 revealed several novel G-protein coupled receptor genes, an HMG-1 remnant and many additional polymorphic microsatellites that were useful in determining the minimal genetic interval for the Mrc locus. Moreover, comparison of B6, BALB/c, A/J and recombinant Mrc alleles restricted the genetic interval to approximately 470 bp and showed that it was also a hotspot for recombination. MCMV challenge of novel NKC recombinant mice demonstrated that MrcB6 was not required for MCMV resistance nor could it directly complement the Ly49BALB haplotype to rescue MCMV susceptibility. Taken together, these data show that while Mrc apparently guides recombination, Ly49H expression is sufficient for MCMV resistance in B6 mice. A direct role for MrcB6 in virus resistance is excluded in the novel mice.
AB - The NK gene complex (NKC) controls murine cytomegalovirus (MCMV) immunity through Cmv1-dependent natural killer (NK) cell responses. Ly49H expression correlates with Cmv1 phenotypes in different inbred strains, is required for MCMV resistance in C57BL/6 (B6) mice, and its interaction with the MCMV encoded m157 protein leads to NK cell-mediated destruction of virus-infected cells. However, genetic mapping studies have previously indicated that Cmv1 should reside in the D6Wum9-16 NKC interval, distal to Ly49h. Since these data suggested that multiple NKC-linked loci could regulate viral immunity, a putative MCMV resistance control (Mrc) locus was pinpointed to within the D6Wum9-16 interval on a NKC-aligned bacterial artificial chromosome (BAC). Sequence analysis of BAC 151 revealed several novel G-protein coupled receptor genes, an HMG-1 remnant and many additional polymorphic microsatellites that were useful in determining the minimal genetic interval for the Mrc locus. Moreover, comparison of B6, BALB/c, A/J and recombinant Mrc alleles restricted the genetic interval to approximately 470 bp and showed that it was also a hotspot for recombination. MCMV challenge of novel NKC recombinant mice demonstrated that MrcB6 was not required for MCMV resistance nor could it directly complement the Ly49BALB haplotype to rescue MCMV susceptibility. Taken together, these data show that while Mrc apparently guides recombination, Ly49H expression is sufficient for MCMV resistance in B6 mice. A direct role for MrcB6 in virus resistance is excluded in the novel mice.
KW - G-protein coupled receptors
KW - Natural killer gene complex
KW - Recombination hotspot
KW - Viral immunity
UR - http://www.scopus.com/inward/record.url?scp=0141924451&partnerID=8YFLogxK
U2 - 10.1007/s00251-003-0591-8
DO - 10.1007/s00251-003-0591-8
M3 - Article
C2 - 12920489
AN - SCOPUS:0141924451
SN - 0093-7711
VL - 55
SP - 370
EP - 378
JO - Immunogenetics
JF - Immunogenetics
IS - 6
ER -