In mammals, B cell functionality is greatly influenced by cytokines released by innate cells, such as macrophages or dendritic cells, upon the early recognition of common pathogen patterns through invariant receptors. B cell activating factor (BAFF) is one of these innate B cell-helper signals and plays a key role in the survival and differentiation of B cells. Although, evolutionarily, teleost fish constitute the first animal group in which adaptive immunity based on Ig receptors is present, fish still rely greatly on innate responses. In this context, we hypothesized that BAFF would play a key role in the control of B cell responses in fish. Supporting this, our results show that teleost BAFF recapitulates mammalian BAFF stimulating actions on B cells, up-regulating the expression of membrane MHC II, improving the survival of fish naïve B cells and antibody secreting cells, and increasing the secretion of IgM. Surprisingly, we also demonstrate that BAFF is not only produced in fish by myeloid cells, but is also produced by a subset of splenic B cells. Thus, if this B cell-produced BAFF proves to be actively regulating this same B cell subset, our findings point to an ancient mechanism to control B cell differentiation and survival in lower vertebrates, which has been silenced in mammals in physiological conditions, but reemerges under pathological conditions, such as B cell lymphomas and autoimmune diseases.

Dendritic cells (DCs) are highly specialized antigen-presenting cells that bridge innate and adaptive immune responses in vertebrates, being key modulators in the initiation of specific responses. Although teleost fish present the main elements of a fully developed adaptive immune system, not many studies have focused on identifying specific DC subsets in teleost species. Previous work from our group identified in rainbow trout (Oncorhynchus mykiss) skin a DC subpopulation co-expressing CD8α and major histocompatibility complex II β on the cell surface. Interestingly, these CD8⁺ DCs expressed common unique markers of mammalian cross-presenting DCs, a DC subset with an important role in antigen presentation and activation of CD8⁺ T cytotoxic lymphocytes. In this study, we have identified a similar DC subset in rainbow trout gills that also transcribes molecules uniquely expressed on diverse mammalian cross-presenting DC populations such as CD8, CD103, CD141, Batf3, IFN regulatory protein 8, and toll-like receptor 3. Hence, we have undertaken a broad phenotypic and functional characterization of this new DC subset that includes the confirmation of novel capacities for DCs in teleost, such an IgM-binding capacity and responsiveness to CD40 ligand. Furthermore, our results show that in gills, this DC subset shows some different phenotypic and functional characteristics when compared with their homologs in the skin, suggesting an adaptation of the cells to different mucosal tissues or different maturation status depending on their location. Our findings contribute to increase our knowledge on fish cross-presenting DCs, an important cell population to take into account for the future design of mucosal vaccination strategies.

Most ligands and receptors from the tumor necrosis factor (TNF) superfamily play very important roles in the immune system. In particular, many of these molecules are essential in the regulation of B cell biology and B cell-mediated immune responses. Hence, in mammals, it is known that many TNF family members play a key role on B cell development, maturation, homeostasis, activation, and differentiation, also influencing the ability of B cells to present antigens or act as regulators of immune responses. Evolutionarily, jawed fish (including cartilaginous and bony fish) constitute the first animal group in which an adaptive immune response based on B cells and immunoglobulins is present. However, until recently, not much was known about the expression of TNF ligands and receptors in these species. The sequences of many members of the TNF superfamily have been recently identified in different species of jawed fish, thus allowing posterior analysis on the role that these ligands and receptors have on B cell functionality. In this review, we summarize the current knowledge on the impact that the TNF family members have in different aspects of B cell functionality in fish, also providing an in depth comparison with functional aspects of TNF members in mammals, that will permit a further understanding of how B cell functionality is regulated in these distant animal groups.

Tumor necrosis factor ligand superfamily members such as B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have been identified in mammals as key regulators of B cell homeostasis and activation. However, the immune functions of APRIL are not as well defined as those of BAFF. Furthermore, while BAFF is present in all vertebrates, APRIL is missing in some animal groups, suggesting that BAFF has compensated the functions of APRIL in these species. In this context, we thought of great interest to explore the effects of APRIL on teleost B cells, given that APRIL appears for the first time in evolution in bony fish. Thus, in this study, we have performed an extensive analysis of the effect of APRIL on B cells using rainbow trout (Oncorhynchus mykiss) as a model species. Our results demonstrate that APRIL induces a specific proliferation of IgM⁺ B cells by itself and increases IgM secretion without promoting a terminal differentiation to plasma cells. APRIL also increased the levels of surface MHC II and augmented the capacity of these cells to process antigen, effects that were exclusively exerted on IgM⁺ B cells. Although our results point to a highly conserved role of APRIL on B cell homeostasis and activation throughout evolution, some specific differential effects have been observed in fish in comparison to the effects of APRIL previously described in mammals. Finally, the effects that APRIL induces on rainbow trout IgM⁺ B cells described in this paper have been compared with those previously reported in response to BAFF.