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TSPAN33 is the last described member of the tetraspanin protein family; it is highly expressed in malignant B cells and is one of the most controversial tetraspanins on regard of its function in leukocytes. In human B cells, we observed that the expression of TSPAN33 is rapidly induced by IL-4 and anti-CD40 stimulation and its antibody-induced cross-linking reduced the cell proliferation rate. Furthermore, by over-expressing TSPAN33 in Raji B cells, we detected dramatic alterations at different membrane features of these lymphocytes. Our results show that TSPAN33 promotes the formation and extension of microvilli and membrane protrusions generated during cell spreading by altering the cortical actin cytoskeleton and the surface expression of LFA-1, CD29 and CD44. In this way, we also demonstrate that TSPAN33 participates in adhesion events such as immune synapse formation with T cells and extracellular matrix substrate adhesion. TSPAN33 belongs to the TspanC8 tetraspanin subgroup, which is associated with the metalloprotease ADAM10 regulating its traffic and activity in different cell membranes. ADAM10 mediates the proteolytic cleavage of several proteins including the Notch receptors. We observed that TSPAN33 does not just alter the expression ADAM10 but also modifies the expression and activity (measured by proliferation and target genes activation assays) of Notch receptors in B cells. Taken together, all these findings demonstrate that TSPAN33 plays a role in the cytoskeleton dynamics and Notch signaling pathway in B cells, by altering different membrane features which in turn modify the surface ADAM10/Notch interactions, regulating its signaling capacity.

We have identified a novel mouse and human cytokine. IL-40 is normally produced in the bone marrow and fetal liver, and by activated B cells. Its sequence predicts a small (~27kDa) secreted protein unrelated to other cytokine gene families, that we have called Interleukin 40 (IL-40). IL40 is only present in mammalian genomes, suggesting a role in mammalian immune responses. Accordingly, IL-40 expression is induced in the mammary gland upon the onset of lactation, and an IL-40−/− mouse exhibits reduced levels of IgA in the serum, gut, feces, and milk. Furthermore, the IL-40−/− mouse has smaller and fewer Peyer’s patches and IgA secreting cells. The gut microbiome of IL-40−/− mice also exhibits altered composition, reflecting the reduced levels of IgA in the gut. We have also determined that B cell precursor populations are altered in the IL-40−/− mouse. Taken together, these observations indicate that IL-40 represents a novel B cell associated cytokine, that plays an important role in the development of humoral immune responses. 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 these diseases.

Chemokines chemotactic molecules that regulate the development of immune responses, There are 48 members of this human gene superfamily and for most we have a good understanding of their biology. Some, however, remain poorly characterized including CXCL17 which was the last ligand of this superfamily to be described. Recently, we reported that CXCL17 is an important mucosal chemokine that exhibits antimicrobial activity and is elevated in the bronchoalveolar lavage fluid (BALf) of patients with idiopathic pulmonary fibrosis. We have now explored the chemotactic properties of CXCL17. In vitro, CXCL17 induces chemotactic responses in monocytic cell lines and in macrophages. We also analyzed CXCL17 effects in vivo and observed that it recruits F4/80+ macrophages to the peritoneal cavity. We have obtained a Cxcl17 (-/-) mouse and observed that it exhibits decreased numbers of macrophages is several mucosal tissues when compared to wild type mice. We conclude that CXCL17 is an important macrophage chemotactic factor. In addition, this information indicates that CXCL17 is likely involved in macrophage recruitment both under homeostatic conditions and also during inflammatory responses. Importantly, CXCL17 is likely to participate in human disease as we have already observed high levels of this chemokine in IPF. Taken together, our data strongly suggests that CXCL17 may be involved in human inflammatory diseases that affect the mucosa.