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Evidence of functional Cd94 polymorphism in a free-living house mouse population

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Abstract

The CD94 receptor, expressed on natural killer (NK) and CD8+ T cells, is known as a relatively non-polymorphic receptor with orthologues in humans, other primates, cattle, and rodents. In the house mouse (Mus musculus), a single allele is highly conserved among laboratory strains, and reports of allelic variation in lab- or wild-living mice are lacking, except for deficiency in one lab strain (DBA/2J). The non-classical MHC-I molecule Qa-1b is the ligand for mouse CD94/NKG2A, presenting alternative non-americ fragment of leader peptides (Qa-1 determinant modifier (Qdm)) from classical MHC-I molecules. Here, we report a novel allele identified in free-living house mice captured in Norway, living among individuals carrying the canonical Cd94 allele. The novel Cd94LocA allele encodes 12 amino acid substitutions in the extracellular lectin-like domain. Flow cytometric analysis of primary NK cells and transfected cells indicates that the substitutions prevent binding of CD94 mAb and Qa-1b/Qdm tetramers. Our data further indicate correlation of Cd94 polymorphism with the two major subspecies of house mice in Europe. Together, these findings suggest that the Cd94LocA/NKG2A heterodimeric receptor is widely expressed among M. musculus subspecies musculus, with ligand-binding properties different from mice of subspecies domesticus, such as the C57BL/6 strain.

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Abbreviations

M. m. :

Mus musculus

B6:

C57BL/6

NKC:

Natural killer gene complex

Qdm:

Qa-1 determinant modifier

KIR:

Killer cell immunoglobulin-like receptor

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Funding

This work was funded internally at NMBU.

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Authors and Affiliations

  1. Faculty of Veterinary Medicine, Department of Food Safety and Infection Biology (MatInf), Norwegian University of Life Sciences (NMBU), Oslo, Norway

    Linn E. Knutsen, Anne K. Storset & Preben Boysen

  2. Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    Erik Dissen, Per C. Saether & Elisabeth Gyllensten Bjørnsen

  3. Research Facility Studenec, Institute of Vertebrate Biology of the Czech Academy of Sciences, Brno, Czech Republic

    Jaroslav Piálek

Authors
  1. Linn E. Knutsen
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  2. Erik Dissen
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  3. Per C. Saether
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  4. Elisabeth Gyllensten Bjørnsen
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  5. Jaroslav Piálek
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  6. Anne K. Storset
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  7. Preben Boysen
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Contributions

LEK, ED, AKS, and PB conceived the study and designed the experiments. LEK, ED, and PB wrote the manuscript, with contributions from JP and AKS. LEK, JP, and PB caught wild mice. LEK, ED, EGB, PCS, and PB performed lab experiments and analyses. The authors thank Stine Braaen, Hanne M. Haatveit, and Grethe M. Johansen at the Norwegian University of Life Sciences for technical assistance.

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Correspondence to Preben Boysen.

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Electronic supplementary material

Supplementary figure 1.

17 nucleotides are substituted in the novel Cd94 allele. Alignment of the Cd94 coding region cDNA sequence of C57BL/6 (AF030311) and the free-living Mus musculus from location A (Loc.A). Identical nucleotides are shaded black and substituted nucleotides white. Exons are indicated by black lines. (PDF 70 kb)

Supplementary figure 2.

Two-color flow cytometry analysis of triple-transfected cells. 293T cells were transiently co-transfected with expression constructs encoding mouse NKG2A-HA, DAP12-FLAG and either the B6 or the LocA allellic versions of CD94 with a C-terminal c-Myc epitope tag, and were analyzed by flow cytometry using mAbs towards c-Myc (FITC) together with CD94 (eFluor 450, top row) or FLAG (AlexaFluor 450, bottom row). (PDF 60 kb)

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Knutsen, L.E., Dissen, E., Saether, P.C. et al. Evidence of functional Cd94 polymorphism in a free-living house mouse population. Immunogenetics 71, 321–333 (2019). https://doi.org/10.1007/s00251-018-01100-x

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