Abstract
rag1−/− zebrafish have been employed in immunological research as a useful immunodeficient vertebrate model, but with only fragmentary evidence for the lack of functional adaptive immunity. rag1-null zebrafish exhibit differences from their human and murine counterparts in that they can be maintained without any specific pathogen-free conditions. To define the immunodeficient status of rag1−/− zebrafish, we obtained further functional evidence on T- and B-cell deficiency in the fish at the protein, cellular, and organism levels. Our developed microscale assays provided evidence that rag1−/− fish do not possess serum IgM protein, that they do not achieve specific protection even after vaccination, and that they cannot induce antigen-specific CTL activity. The mortality rate in non-vaccinated fish suggests that rag1−/− fish possess innate protection equivalent to that of rag1+/− fish. Furthermore, poly(I:C)-induced immune responses revealed that the organ that controls anti-viral immunity is shifted from the spleen to the hepatopancreas due to the absence of T- and B-cell function, implying that immune homeostasis may change to an underside mode in rag-null fish. These findings suggest that the teleost relies heavily on innate immunity. Thus, this model could better highlight innate immunity in animals that lack adaptive immunity than mouse models.
Highlights
Recombination-activating gene 1 plays an essential role in the rearrangement and recombination of immunoglobulins and T-cell receptor (TCR) genes
These findings indicate that the rag1-null fish exhibits one of the typical phenotypes of rag1-deficient animals, it remains unclear whether they lack the ability to produce immunoglobulin, whether they are protected by vaccination, and whether they exhibit specific cell-mediated immunity, such as cytotoxic T cell function
These results indicate that IgM is absent in serum from rag1−/− fish
Summary
Recombination-activating gene 1 (rag1) plays an essential role in the rearrangement and recombination of immunoglobulins and T-cell receptor (TCR) genes. Several groups have utilized this fish for immunological studies and demonstrated their functions in some pathogenic models[17,18,19] The observations in these studies and our findings suggest that the rag1-null zebrafish possess more robust rag1-independent immunity than mammalian models. The V segments of TCR and immunoglobulin mRNA were not found in the null animals These findings indicate that the rag1-null fish exhibits one of the typical phenotypes of rag1-deficient animals, it remains unclear whether they lack the ability to produce immunoglobulin, whether they are protected by vaccination, and whether they exhibit specific cell-mediated immunity, such as cytotoxic T cell function. The present study sought to establish assays for analyzing these questions at the protein and cellular levels for small fish, validating T- and B-cell deficiency, investigating the expression profiles of cytokines in rag1-null fish, and discussing differences in the balance of adaptive and innate immunity between mammals and teleosts
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