Abstract
Related interleukin-2, -15, and -15-like (IL-2, -15, and -15L) are ancient cytokines, with all three genes surviving in extant fish and some mammals. The present study is the first to identify IL-15L functions, namely in rainbow trout. In isolated trout splenocytes, and in vivo, purified recombinant IL-15L+IL-15Rα molecules induced expression of IL-4 and IL-13 homologs, which are markers of type 2 immunity. In contrast, trout IL-15 stimulated type 1 immunity markers, thus IL-15 and IL-15L can have opposing functions. Trout IL-15L was more dependent on “in trans” presentation by the receptor chain IL-15Rα than IL-15, and stimulated CD4−CD8−(IgM−) lymphocytes from thymus and spleen. We propose an important role for IL-15L early in the type 2 immunity cytokine cascade. Trout IL-2 and IL-15 exhibited features reminiscent of their mechanistic and functional dichotomy observed in mammals; for example, IL-15 but not IL-2 required a receptor alpha chain (only IL-15Rα in the case of fish) for its stability, and only IL-15 was efficient in stimulating lymphocytes from mucosal tissues. Data suggest that IL-15L and IL-15 may be particularly effective in stimulating innate lymphocyte type 2 cells (ILC2) and natural killer (NK) cells, respectively, but further identification of the cell types is needed. An interesting finding different from in mammals was the efficient stimulation of CD4+CD8+ thymocytes by IL-2. In short, this study presents fundamental information on the evolution of the IL-2/15/15L cytokine family.
Highlights
Interleukin 2 (IL-2) was one of the first cytokines to be characterized
Two rainbow trout IL-15L genes, IL-15La, and IL-15Lb, could be identified in genomic sequence databases (Figure 1) and were amplified from cDNA (Supplementary Files 1A,B). They map to the rainbow trout reference genome chromosomes 27 and 24, which have been recognized as a pair of chromosomes sharing ohnologous regions derived from a whole genome duplication early in the evolution of salmonid fishes [40]
Despite variation between trout individuals, rather consistent findings were that trout IL-15Lb expression was relatively high in gill, and both trout IL-15La and IL-15Lb expression were relatively low in head kidney (Figure 2 and Supplementary File 1C)
Summary
Interleukin 2 (IL-2) was one of the first cytokines to be characterized This was due to the remarkable power of IL-2 to induce and sustain T lymphocyte proliferation in vitro, and IL-2 was originally named “T cell growth factor” (TCGF) [1,2,3]. Interleukin-15-Like Induces Type 2 Immunity important tools for in vitro culturing of lymphocytes and for treating disease in the clinic or in preclinical models [reviewed in [8]]. How mammalian IL-2 vs IL-15 functions and mechanisms are organized is only partially understood, and analysis of this cytokine family in non-mammalian species may provide additional insights. In rodents and higher primates only an IL15L pseudogene was found, and IL-15L function is not expected in those species [13]
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