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Analysis of shark NCR3 family genes reveals primordial features of vertebrate NKp30

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Abstract

Natural killer (NK) cells play major roles in innate immunity against viruses and cancer. Natural killer receptors (NKR) expressed by NK cells recognize foreign- or self-ligands on infected and transformed cells as well as healthy cells. NKR genes are the most rapidly evolving loci in vertebrates, and it is generally difficult to detect orthologues in different taxa. The unique exception is NKp30, an activating NKR in mammals that binds to the self-ligand B7H6. The NKp30-encoding gene, NCR3, has been found in most vertebrates including sharks, the oldest vertebrates with human-type adaptive immunity. NCR3 has a special, non-rearranging VJ-type immunoglobulin superfamily (IgSF) domain that predates the emergence of the rearranging antigen receptors. Herein we show that NCR3 loci are linked to the shark major histocompatibility complex (MHC), proving NCR3’s primordial association with the MHC. We identified eight subtypes of differentially expressed highly divergent shark NCR3 family genes. Using in situ hybridization, we detected one subtype, NS344823, to be expressed by predominantly single cells outside of splenic B cell zones. The expression by non-B cells was also confirmed by PCR in peripheral blood lymphocytes. Surprisingly, high expression of NS344823 was detected in the thymic cortex, demonstrating NS344823 expression in developing T cells. Finally, we show for the first time that shark T cells are found as single cells or in small clusters in the splenic red pulp, also unassociated with the large B cell follicles we previously identified.

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Data availability

All sequences had been deposited to GenBank (accession numbers MT914154-MT914170). Reagents generated from these studies are available to the public upon request.

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Funding

MEJ and JK were supported by the University of Maryland Scholars Program, an initiative of the University of Maryland: MPowering the State. MFF and YO are supported by National Institutes of Health Grants AI140-326-27 and AI02877. MFC was supported by National Science Foundation Grants IOS 1257829 and IOS-1656870.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Maryland Baltimore, Baltimore, MD, 21201, USA

    Allison Kinlein, Morgan E. Janes, Jacob Kincer, Hanover Matz, Jianxin Sui, Martin F. Flajnik & Yuko Ohta

  2. Centro de Investigacão Em Biodiversidade E Recursos Genéticos, CIBIO-InBIO, Campus Agrário de Vairão, Universidade Do Porto, Vairão, Porto, Portugal

    Tereza Almeida

  3. Departamento de Biologia, Faculdade de Ciências da Universidade Do Porto, Porto, Portugal

    Tereza Almeida

  4. Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, 77843, USA

    Michael F. Criscitiello

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  1. Allison Kinlein
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  2. Morgan E. Janes
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  3. Jacob Kincer
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  4. Tereza Almeida
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  6. Jianxin Sui
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  7. Michael F. Criscitiello
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  8. Martin F. Flajnik
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  9. Yuko Ohta
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Contributions

Three authors, Allison Kinlein, Morgan E. James, and Jacob Kincer, share the first authorship. The study conception and design were conducted by Martin Flajnik and Yuko Ohta. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by Morgan Janes and further modified by Yuko Ohta and Martin Flajnik. All authors commented on the manuscript preparation and approved the final edits.

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Correspondence to Yuko Ohta.

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All procedures performed in studies involving animals were approved by Institutional Animal Care and Use Committee (IACUC) at University of Maryland.

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Kinlein, A., Janes, M.E., Kincer, J. et al. Analysis of shark NCR3 family genes reveals primordial features of vertebrate NKp30. Immunogenetics 73, 333–348 (2021). https://doi.org/10.1007/s00251-021-01209-6

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