The adaptive immune system consists of two types of lymphocytes: T and B cells. These two lymphocytes originate from a common precursor, yet are fundamentally different with B cells mediating humoral immunity while T cells mediate cell mediated immunity. In cytokine production, naïve T cells produce multiple cytokines upon activation while naïve activated B cells do not. B cells are capable of producing cytokines, but their cytokine production depends on their differentiation state and activation conditions. Hence, unlike T cells that can produce a large amount of cytokines upon activation, B cells require specific differentiation and activation conditions to produce cytokines. Many cytokines act on B cells as well. Here, we discuss several cytokines and their effects on B cells including: Interleukins, IL-7, IL-4, IL-6, IL-10, and Interferons, IFN-α, IFN-β, IFN-γ. These cytokines play important roles in the development, survival, differentiation and/or proliferation of B cells. Certain chemokines also play important roles in B cell function, namely antibody production. As an example, we discuss CCL28, a chemokine that directs the migration of plasma cells to mucosal sites. We conclude with a brief overview of B cells as cytokine producers and their likely functional consequences on the immune response.

Cytokines are important molecules that regulate the ontogeny and function of the immune system. They are small secreted proteins usually produced upon activation of cells of the immune system, including lymphocytes and myeloid cells. Many cytokines have been described, and several have been recognized as pivotal players in immune responses and in human disease. In fact, several anticytokine antibodies have proven effective therapeutics, especially in various autoimmune diseases. In the last 15 years, new cytokines have been described, and many remain poorly understood. Among the most recent cytokines discovered are interleukins-30 (IL-30) to IL-40. Several of these are members of other cytokine superfamilies, including several IL-1 superfamily members (IL-33, IL-36, IL-37, and IL-38) as well as several new members of the IL-12 family (IL-30, IL-35, and IL-39). The rest (IL-31, IL-32, IL-34, and IL-40) are encoded by genes that do not belong to any cytokine superfamily. Our aim of this review was to present a concise version of the information available on these novel cytokines to facilitate their understanding by members of the immunological community.

We have described a novel cytokine encoded by a gene called Meteorin-like (Metrnl). Metrnl is a small (~27kDa) secreted protein expressed by activated macrophages and barrier tissues (mucosa, skin). Metrnl production by bone marrow macrophages is induced by several cytokines including TNFα, IL-17α, IL-12 and IL-4 and inhibited by IFNγ and TGFβ. Metrnl expression in macrophages is also induced by lipopolysaccharide (LPS) and its levels in circulation are associated with inflammatory responses in vivo. Furthermore, Metrnl regulates the production of several cytokines and chemokines in macrophages. We have produced a Metrnl−/− mouse which is viable and shows normal development. However, it exhibits dysregulated cytokine production, alterations in IgG production, and is highly susceptible to LPS in a sepsis model. Furthermore, older Metrnl−/− mice develop inflammatory lesions, suggesting that Metrnl participates in the control of inflammatory responses. Taken together, these observations indicate that Metrnl encodes a novel immunoregulatory cytokine associated with inflammatory responses that we have designated Meteorin Beta.

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We describe a novel B cell–associated cytokine, encoded by an uncharacterized gene (C17orf99; chromosome 17 open reading frame 99), that is expressed in bone marrow and fetal liver and whose expression is also induced in peripheral B cells upon activation. C17orf99 is only present in mammalian genomes, and it encodes a small (~27-kDa) secreted protein unrelated to other cytokine families, suggesting a function in mammalian immune responses. Accordingly, C17orf99 expression is induced in the mammary gland upon the onset of lactation, and a C17orf99−/− mouse exhibits reduced levels of IgA in the serum, gut, feces, and lactating mammary gland. C17orf99−/− mice have smaller and fewer Peyer’s patches and lower numbers of IgA-secreting cells. The microbiome of C17orf99−/− mice exhibits altered composition, likely a consequence of the reduced levels of IgA in the gut. Although naive B cells can express C17orf99 upon activation, their production increases following culture with various cytokines, including IL-4 and TGF-β1, suggesting that differentiation can result in the expansion of C17orf99-producing B cells during some immune responses. Taken together, these observations indicate that C17orf99 encodes a novel B cell–associated cytokine, which we have called IL-40, that plays an important role in humoral immune responses and may also play a role in B cell development. Importantly, IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observations suggest that it may play a role in the pathogenesis of certain human diseases.