Abstract: The present invention provides human binding proteins and antigen-binding fragments thereof that specifically bind to the human interleukin-21 receptor (IL21R), and uses therefore. The invention further provides methods to predict whether the binding proteins of the invention may take on agonistic activities in vivo and produce a cytokine storm. In addition, the invention provides methods for determining whether an anti-IL21R binding protein is a neutralizing anti-IL21R binding protein, based on the identification of several IL21-responsive genes. The binding proteins can act as, e.g., antagonists of IL21R activity, thereby modulating immune responses in general, and those mediated by IL21R in particular.