To study the potential roles of CD40L in immune responses, we generated CD40L-deflcient mice by gene targeting. Similar to the effecta of CD4OL mutations in humans (hype+ IgM syndrome), CD40L-deflcient mice have a decreased IgM response to thymus-dependent antigens, fail altogether to produce an antigen-specific IgGl response following immunization, yet respond normally to a T-independent antigen, TNP-Ficoll. More over, these mice do not develop germinal centers in response to thymus-dependent antigens, suggesttng an inabillty to develop memov B cell responses. Although CD40L-deficient mice have low levels of most circulating immunoglobulln isotypes, they do not exhibit the spontaneous hyper-IgM syndrome seen in humans, at least up to 12 weeks of age. In summary, our study confirms the important role of CD40-CD40L interactions in thymus-dependent humorel immune responses and germinal center formation.