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MyD88 is an essential regulator of NK cell-mediated clearance of MCMV infection. Mol Immunol 2021 09;137:94-104

Date

07/10/2021

Pubmed ID

34242922

DOI

10.1016/j.molimm.2021.07.001

Scopus ID

2-s2.0-85109126048

Abstract

The signaling adapter MyD88 is critical for immune cell activation in response to viral or bacterial pathogens via several TLRs, IL-1I?R and IL-18R. However, the essential role of MyD88 during activations mediated by germline-encoded NK cell receptors (NKRs), such as Ly49H or NKG2D, has yet to be investigated. To define the NK cell-intrinsic function of MyD88, we generated a novel NK cell conditional knockout mouse for MyD88 (Myd88fl/flNcr1Cre/+). Phenotypic characterization of these mice demonstrated that MyD88 is dispensable for NK cell development and maturation. However, the MyD88-deficient NK cells exhibited significantly reduced cytotoxic potentials in vivo. In addition, the lack of MyD88 significantly reduced the NKG2D-mediated inflammatory cytokine production in vitro. Consistent with this, mice lacking MyD88 were unable to respond and clear MCMV infection. Transcriptomic analyses of splenic NK cells following MCMV infection revealed that inflammatory gene signatures were upregulated in Ly49H+. In contrast, Ly49H- NK cells have significant enrichment in G2M checkpoint genes, revealing distinct transcriptomic profiles of these subsets. Our results identify a central role for MyD88 in Ly49H-dependent gene signatures, including alterations in genes regulating proliferation in Ly49H+ NK cells. In summary, our study reveals a previously unknown function of MyD88 in Ly49H-dependent signaling and in vivo functions of NK cells.

Author List

Dixon KJ, Siebert JR, Wang D, Abel AM, Johnson KE, Riese MJ, Terhune SS, Tarakanova VL, Thakar MS, Malarkannan S

Authors

Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Vera Tarakanova PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Proliferation
Cytokines
Female
Herpesviridae Infections
Inflammation
Killer Cells, Natural
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Muromegalovirus
Myeloid Differentiation Factor 88
NK Cell Lectin-Like Receptor Subfamily K
Receptors, Natural Killer Cell
Signal Transduction
Transcriptome