The requirements for interleukin 2 (IL2) and other T cell-derived helper factors in the responses of unprimed and antigen-primed B cells to sheep erythrocytes were investigated. Unprimed B cells required both IL2 and additional factor(s), hereafter referred to as T cell-replacing factor (TRF), in addition to specific antigen, for antibody production. IL2 was required only during the early stages (approximately equal to 24 h) of culture while TRF was necessary only after this time and was then required throughout the remaining culture period. IL2 stimulated the appearance of Thy-1+ cells in unprimed "B cell" populations which could substitute for the function of IL2, implicating an indirect role, at least in part, for IL2 in the TRF assay. Furthermore, in contrast to the results with unprimed B cells, primed B cells required only late-acting TRF for optimal antibody responses. We suggest that IL2 activates residual T cells or precursors of T cells in B cell populations which then function, in the presence of specific antigen, to render B cells receptive to T cell-derived factors which promote B cell growth and differentiation.