© 2008 Nature Publishing Group production evolved primarily to downregulate vigorous adaptive pathogenspecific immune responses (involving combined TLR, BCR and CD40 signalling) and would also contribute to the resolution of autoimmune disease exacer bation (see part a of figure). By contrast, naive B cells produce IL10 when stimulated in a ‘bystander’activation context through non cognate interaction with an activated T cell (CD40 signalling only, independent of either TLR or BCR signalling). This IL10 produc tion by naive B cells (that normally harbor the autoreactive Bcell repertoire) is probably most relevant to early Bcell–Tcell interac tions and the maintenance of normal immune homeostasis (see part b of figure). So, in the context of autoimmune disease regulation, naive Bcell IL10 production may function primarily in the prevention of inflammatory responses in autoimmune disease, whereas memory Bcell IL10 production may func tion primarily as a mechanism of resolving active disease exacerbation. Evidence is mounting that Bcell IL10 can regulate immune responses in both health and disease. As Fillatreau et al. note in their Opinion paper, TLRmediated IL10 induc tion represents one such context. It is likely that Bcellderived regulatory IL10 has evolved to serve distinct immune functions, and that these functions are in turn care fully regulated in a cellsubset and context dependent manner.