We propose a model where human dendritic cell (DC) subsets control, in a coordinated fashion, B cell growth and differentiation. Plasmacytoid DCs drive memory B cell differentiation into effector plasma cell via type I interferon and IL-6. Type I interferon activates myeloid DCs that regulate B cell priming and acquisition of memory phenotype via IL-12, IL-6 and Blys/Baff. This model also integrates the role of antigen-specific T cells activated by myeloid DCs. Thus, protective humoral immunity results from a highly coordinated interplay of human DC subsets. This interplay may explain the spreading of immune response to deal with antigenic drift and to maintain an active immunity against mutating microbe. It may also provide an explanation for spreading of the autoimmune repertoire as autoimmunity develops.