CD22 is a glycoprotein that associates with the B cell antigen receptor and acts as a negative regulator of receptor signaling; its extracellular domain binds α2,6‐linked sialoglycoconjugates. Here we show that B cell activation by antigen displayed on the surface of a target cell is depressed if the target co‐expresses α2,6‐sialoglycoconjugates: this inhibition is dependent on CD22. Since sialylation is largely a feature of higher eukaryotes with α2,6‐sialyltransferase increasing during inflammation, we propose that the CD22 / sialoglycoconjugate interaction allows context‐dependent B cell activation, possibly acting as a crude discriminator of self in order to dampen B cell autoreactivity and the initiation of autoimmunity.