Collaborative interactions between B lymphocytes and CD4+ helper T cells are necessary for the induction of Ab responses to most protein Ag and for the generation of memory B cells in germinal centers. To study the role of the CD4 molecule in the germinal center response and in the development of B cell memory, we have investigated T helper function in the initiation and maturation of humoral immunity in CD4-deficient mice. In the absence of CD4+ T cells, immunization with thymus-dependent Ag was able to induce germinal center formation and Ig somatic hypermutation. In addition, Ag-driven affinity maturation and development of B cell memory were largely intact in CD4-deficient mice. Thus, CD4-deficient T helper cells are able to collaborate with Ag-activated B cells to elicit the germinal center reaction, switch on the mutational machinery, and deliver signals necessary for B cell memory development.