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Evolution of the CD4 Family: Teleost Fish Possess Two Divergent Forms of CD4 in Addition to Lymphocyte Activation Gene-3¹

Kerry J. Laing^*,, Jun J. Zou, Maureen K. Purcell, Ruth Phillips, Christopher J. Secombes and John D. Hansen^2,*,

^* Department of Pathobiology, University of Washington, Seattle WA 98195; School of Biological Sciences, University of Aberdeen, Aberdeen, United Kingdom; Western Fisheries Research Center, U.S. Geological Survey Biological Resources Division, Seattle, WA 98115; and Washington State University, School of Biological Sciences, Vancouver, WA 98686

The T cell coreceptor CD4 is a transmembrane glycoprotein belonging to the Ig superfamily and is essential for cell-mediated immunity. Two different genes were identified in rainbow trout that resemble mammalian CD4. One (trout CD4) encodes four extracellular Ig domains reminiscent of mammalian CD4, whereas the other (CD4REL) codes for two Ig domains. Structural motifs within the amino acid sequences suggest that the two Ig domains of CD4REL duplicated to generate the four-domain molecule of CD4 and the related gene, lymphocyte activation gene-3. Here we present evidence that both of these molecules in trout are homologous to mammalian CD4 and that teleosts encode an additional CD4 family member, lymphocyte activation gene-3, which is a marker for activated T cells. The syntenic relationships of similar genes in other teleost and non-fish genomes provide evidence for the likely evolution of CD4-related molecules in vertebrates, with CD4REL likely representing the primordial form in fish. Expression of both CD4 genes is highest in the thymus and spleen, and mRNA expression of these genes is limited to surface IgM^– lymphocytes. consistent with a role for T cell functionality. Finally, the intracellular regions of both CD4 and CD4REL possess the canonical CXC motif involved in the interaction of CD4 with p56LCK, implying that similar mechanisms for CD4⁺ T cell activation are present in all vertebrates. Our results therefore raise new questions about T cell development and functionality in lower vertebrates that cannot be answered by current mammalian models and, thus, is of fundamental importance for understanding the evolution of cell-mediated immunity in gnathosomes.

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¹ This work was supported by Biotechnology and Biological Sciences Research Council Grant BB/C506021/1 (to C.J.S.) and National Science Foundation Molecular and Cellular Biosciences Grant 0453924 (to J.D.H.).

² Address correspondence and reprint requests to Dr. John D. Hansen, Western Fisheries Research Center, U.S. Geological Survey Biological Resources Division, 6505 Northeast 65th Street, Seattle, WA 98115. E-mail address: jdh25{at}u.washington.edu

³ Abbreviations used in this paper: LAG-3, lymphocyte activation gene-3; ARP, acidic ribosomal protein; BAC, bacterial artificial chromosome; EST, expressed sequence tag; qPCR, quantitative RT-PCR; sIgM, surface IgM.