RESUMEN
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.
Asunto(s)
Inmunidad , Inmunomodulación , Interleucina-15/genética , Interleucina-15/metabolismo , Secuencia de Aminoácidos , Animales , Bovinos , Expresión Génica , Glicosilación , Células HEK293 , Humanos , Inmunidad/genética , Inmunofenotipificación , Interleucina-15/química , Subunidad alfa del Receptor de Interleucina-15/genética , Subunidad alfa del Receptor de Interleucina-15/metabolismo , Interleucina-2/genética , Interleucina-2/metabolismo , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Modelos Moleculares , Filogenia , Conformación Proteica , Factor de Transcripción STAT5/metabolismo , Análisis de Secuencia de ADN , Bazo/citología , Bazo/inmunología , Bazo/metabolismo , Relación Estructura-Actividad , Timocitos/inmunología , Timocitos/metabolismo , TruchaRESUMEN
Cell-mediated cytotoxicity is one of the major mechanisms by which vertebrates control intracellular pathogens. Two cell types are the main players in this immune response, natural killer (NK) cells and cytotoxic T lymphocytes (CTL). While NK cells recognize altered target cells in a relatively unspecific manner CTLs use their T cell receptor to identify pathogen-specific peptides that are presented by major histocompatibility (MHC) class I molecules on the surface of infected cells. However, several other signals are needed to regulate cell-mediated cytotoxicity involving a complex network of cytokine- and ligand-receptor interactions. Since the first description of MHC class I molecules in teleosts during the early 90s of the last century a remarkable amount of information on teleost immune responses has been published. The corresponding studies describe teleost cells and molecules that are involved in CTL responses of higher vertebrates. These studies are backed by functional investigations on the killing activity of CTLs in a few teleost species. The present knowledge on teleost CTLs still leaves considerable room for further investigations on the mechanisms by which CTLs act. Nevertheless the information on teleost CTLs and their regulation might already be useful for the control of fish diseases by designing efficient vaccines against such diseases where CTL responses are known to be decisive for the elimination of the corresponding pathogen. This review summarizes the present knowledge on CTL regulation and functions in teleosts. In a special chapter, the role of CTLs in vaccination is discussed.
