UC Irvine

We describe a novel B cell-associated cytokine, encoded by an uncharacterized gene (C17orf99), whose expression is induced in B cells upon activation. C17orf99 is only present in mammalian genomes, and it encodes a small (~27kDa) 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. While naïve B cells can express C17orf99 upon activation, their production increases following culture with various cytokines, including IL4 and TGF-β, 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 Interleukin-40, that plays an important role in the development of humoral immune responses. Importantly, IL-40 is also expressed by human activated B cells and by several human B cell lymphomas. The latter observation suggests that it may play a role in the pathogenesis of certain human diseases.