Review Form, function and phylogenetics of NITRs in bony fish Jeffrey A. Yoder * Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA Contents 1. Introduction ..................................................................................................... 135 2. Inhibitory and activating forms of NITRs .............................................................................. 136 3. The immunoglobulin domains of NITRs ............................................................................... 137 4. Expression of NITRs ............................................................................................... 137 5. NITR ligands ..................................................................................................... 140 6. Identification of NITR cDNAs from salmon, cod, halibut, lake whitefish and stickleback......................................... 141 7. Recent evolution of NITRs within teleosts ............................................................................. 141 8. On the origins of NITRs ............................................................................................ 142 9. Summary ....................................................................................................... 143 Acknowledgements ............................................................................................... 143 References ...................................................................................................... 143 1. Introduction The prototypic NITR cDNA was cloned more than 12 years ago by Rast, Haire and Litman from the Southern pufferfish (Spheroides nephelus) in a search to identify variable (V) domain containing genes that do not undergo V(D)J recombination [1]. This NITR cDNA, ‘‘Sn193’’ encodes an N-terminal extracellular V domain adjacent to a joining (J) domain, a C-terminal extracellular intermediate (I) domain (previously termed V-like C2 or V/C2 domain), a transmembrane domain and a cytoplasmic tail possessing an immunoreceptor tyrosine-based inhibition motif (ITIM) and a second ITIM-like (itim) sequence. Subsequent studies Developmental and Comparative Immunology 33 (2009) 135–144 ARTICLE INFO Article history: Received 31 July 2008 Accepted 8 September 2008 Available online 7 October 2008 Keywords: Teleost Innate immunity Natural killer receptors ITIM ITSM DAP12 CD8 KIR ABSTRACT Novel immune-type receptors (NITRs) are encoded by clusters of multigene families and have been identified in multiple bony fish species. All NITRs possess one extracellular immunoglobulin (Ig) domain of the variable (V) type and recent crystal structures of NITR V domains demonstrate their high degree of similarity to V domains of antigen receptors. Many NITRs possess a second extracellular Ig domain of the intermediate (I) type which helps differentiate NITRs from other V domain receptors. The majority of NITRs are type I transmembrane receptors; however, a small number are predicted to encode secreted proteins. Based on their sequence and structure, NITRs have been proposed to be ‘‘functional orthologs’’ of mammalian natural killer receptors (NKRs). Like NKRs, most NITRs possess short functional motifs permitting their classification as inhibitory or activating. NITRs lacking these motifs are functionally ambiguous. Inhibitory and activating NKRs utilize opposing signaling mechanisms to influence the response of NK cells to target cells; studies employing recombinant NITRs suggest that these signaling pathways are conserved between NKRs and NITRs. An analysis of all published NITR sequences demonstrates the conserved nature of multiple residues within the NITR Ig domains permitting the identification of NITR ESTs from salmon, cod, halibut, lake whitefish and stickleback species. Complete data sets of NITRs from the sequencing of the zebrafish and medaka genomes provide insight into the evolution of the NITRs within bony fish species. It is likely that all teleost species encode NITRs which function within innate immunity to regulate cell mediated cytotoxicity. ß 2008 Elsevier Ltd. All rights reserved. * Tel.: +1 919 515 7406; fax: +1 919 513 7301. E-mail address: Jeff_Yoder@ncsu.edu. Contents lists available at ScienceDirect Developmental and Comparative Immunology journal homepage: www.elsevier.com/locate/dci 0145-305X/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.dci.2008.09.004