The Interplay between Hedgehog Signalling and BMP Signalling in Regulating B cell Development

Morphogens play a significant role in the modulation of cell fate and development and are expressed in all tissue at some point during development. Recent studies suggest that expression of two morphogens, Hedgehog (Hh) and Bone Morphogenetic Protein (BMP), may influence immune cell development in the periphery which is consistent with the finding that Hh is expressed by splenic stromal cells. In addition, preliminary data obtained at UEL suggest that Hh signalling may provide a positive signal in early peripheral B cell development in terms of activation and survival but may then deliver a later negative immunoregulatory signal capable of dampening down the immune response. This may occur as a consequence of the ability of Hh signalling to upregulate expression of BMP. Although Hh and BMP signalling have both been shown to play a role in immune cell development independently, little is known regarding the interplay between the two morphogens and the role this may play in directing an immune response to antigen. In this study murine splenic B cells were cultured in the presence of a signal for B cell activation (anti-IgM and anti-CD40) together with recombinant Sonic Hedgehog protein (rShh) and a BMP inhibitor, Noggin. These experiments were designed in order to elucidate whether it is necessary for Hh signalling to upregulate the expression of BMP for an effective B cell response to take place. We observed that expression of both Hh and BMP is required for efficient activation and survival of B cells at 18 hours post stimulus whilst expression of BMP plays a more dominant role in the later stages of B cell development. Abrogation of BMP signalling led to a significant skewing in the development of certain B cell subsets. Further analysis revealed a potential role for BMP-2 in particular during splenic B cell development, expression of which was significantly upregulated in the presence of exogenous Hh. Overall, our findings suggest that there is indeed an interplay between Hh and BMP signalling in driving appropriate B cell development.