Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection

PLoS Pathogens

Michael G. Brown¹  William Nash¹  Jeffrey Teoh¹  Heather Lee¹  Charles R. Farber¹  Claudia Rival¹  Michael D. Stadnisky²  Alyssa Lundgren Gillespie³  Monique Anderson³  Hairong Wei⁴  Kenneth Tung⁴  Jessica Prince⁴  Awndre Gamache⁵ 

[1] Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, United States of America;Department of Biology, University of Virginia, Charlottesville, Virginia, United States of America;Department of Medicine, Division of Nephrology, University of Virginia, Charlottesville, Virginia, United States of America;Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America;Department of Pathology, University of Virginia, Charlottesville, Virginia, United States of America

关键词: NK cells;    Spleen;    Quantitative trait loci;    Body weight;    Mammalian genomics;    Immune response;    Immune cells;    Major histocompatibility complex;   

DOI  :  10.1371/journal.ppat.1005419

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The MHC class I Dk molecule supplies vital host resistance during murine cytomegalovirus (MCMV) infection. Natural killer (NK) cells expressing the Ly49G2 inhibitory receptor, which specifically binds Dk, are required to control viral spread. The extent of Dk-dependent host resistance, however, differs significantly amongst related strains of mice, C57L and MA/My. As a result, we predicted that relatively small-effect modifier genetic loci might together shape immune cell features, NK cell reactivity, and the host immune response to MCMV. A robust Dk-dependent genetic effect, however, has so far hindered attempts to identify additional host resistance factors. Thus, we applied genomic mapping strategies and multicolor flow cytometric analysis of immune cells in naive and virus-infected hosts to identify genetic modifiers of the host immune response to MCMV. We discovered and validated many quantitative trait loci (QTL); these were mapped to at least 19 positions on 16 chromosomes. Intriguingly, one newly discovered non-MHC locus (Cmv5) controlled splenic NK cell accrual, secondary lymphoid organ structure, and lymphoid follicle development during MCMV infection. We infer that Cmv5 aids host resistance to MCMV infection by expanding NK cells needed to preserve and protect essential tissue structural elements, to enhance lymphoid remodeling and to increase viral clearance in spleen.

【 授权许可】

CC BY