Journal
JOURNAL OF IMMUNOLOGY
Volume 196, Issue 11, Pages 4522-4535Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1600222
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Funding
- U.S. Department of Agriculture [USDA-NRI-2013-01107]
- National Science Foundation [NSF-IOS-1457282]
- National Institutes of Health [2R01GM085207-05]
- Japan Society for the Promotion of Science Postdoctoral Fellowship
- Institut National de la Recherche Agronomique
- European Commission under the Work Programme of the 7th Framework Programme for Research and Technological Development of the European Union [311993 TARGETFISH]
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [1457282] Funding Source: National Science Foundation
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Tetrapods contain a single CD4 coreceptor with four Ig domains that likely arose from a primordial two-domain ancestor. Notably, teleost fish contain two CD4 genes. Like tetrapod CD4, CD4-1 of rainbow trout includes four Ig domains, whereas CD4-2 contains only two. Because CD4-2 is reminiscent of the prototypic two-domain CD4 coreceptor, we hypothesized that by characterizing the cell types bearing CD4-1 and CD4-2, we would shed light into the evolution and primordial roles of CD4-bearing cells. Using newly established mAbs against CD4-1 and CD4-2, we identified two bona-fide CD4(+) T cell populations: a predominant lymphocyte population coexpressing surface CD4-1 and CD4-2 (CD4 double-positive [DP]), and a minor subset expressing only CD4-2 (CD4-2 single-positive [SP]). Although both subsets produced equivalent levels of Th1, Th17, and regulatory T cell cytokines upon bacterial infection, CD4-2 SP lymphocytes were less proliferative and displayed a more restricted TCR beta repertoire. These data suggest that CD4-2 SP cells represent a functionally distinct population and may embody a vestigial CD4(+) T cell subset, the roles of which reflect those of primeval CD4(+) T cells. Importantly, we also describe the first CD4(+) monocyte/macrophage population in a nonmammalian species. Of all myeloid subsets, we found the CD4(+) population to be the most phagocytic, whereas CD4(+) lymphocytes lacked this capacity. This study fills in an important gap in the knowledge of teleost CD4-bearing leukocytes, thus revealing critical insights into the evolutionary origins and primordial roles of CD4(+) lymphocytes and CD4(+) monocytes/macrophages.
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