Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response

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.

Multiomics Provide Insights into the Key Molecules and Pathways Involved in the Physiological Adaptation of Atlantic Salmon (Salmo salar) to Chemotherapeutic-Induced Oxidative Stress

“…Some of the DEGs that significantly overlapped between the SE and LE groups, notably in the gills, have key functions in mucosal defence, including il15rα, the putative receptor for IL-15. The roles of IL-15L and IL-15Rα in Type 2 immunity have recently been reported in fish [41], and this study points to the possibility that it may also be important in immunity to oxidative stress. In mammalian systems, the IL-15 myokine has been implicated to have a protective effect against H 2 O 2 -mediated oxidative stress [42].…”

Transcriptomics of early responses to purified Piscine orthoreovirus-1 in Atlantic salmon (Salmo salar L.) red blood cells compared to non-susceptible cell lines

“…In contrast to rainbow trout RBC, which were shown to express IL1β , IL8 and IFNγ in response to infectious hematopoietic necrosis virus (IHNV) and thermal stress, A. salmon RBC demonstrated high transcript levels of only IL15 and IL34 ( 7 , 36 ). Studies on the characterization of IL15 in rainbow trout suggested its involvement in CD4+ T cell survival, where it induces IFNγ through a STAT5p - dependent signaling pathway ( 60 , 61 ). The function of IL34 is modestly explored in salmonids.…”

The implications of IL-15 trans-presentation on the immune response

“…Interestingly, the ability of IL-2 to act primarily as a soluble cytokine and of IL-15 as a heterodimer with IL-15Rα was already established in fish. Thus, IL-2, IL-15, IL-15Rα and the IL-15 transpresentation system evolved at least 460 million years ago, with a shared IL-15L between cattle and trout (Gunimaladevi, Savan, Sato, Yamaguchi, & Sakai, 2007;Wang, Holland, Carrington, Zou, & Secombes, 2007;Yamaguchi et al, 2020).…”