We examined the role of antigen-presenting B lymphocytes using panels of antigen-specific CD4+8-T-lymphocyte clones (TLC). All 19 TLC showed a class II major histocompatibility complex-encoded (HLA-II) restricted proliferation to antigen presented by antigen-presenting cells (APC) from the monocyte fraction of peripheral blood. Only six TLC were effectively activated by antigen presented by autologous B lymphocytes activated by EBV transformation. This failure of B lymphocytes was not due to: (i) a high degree of cell surface sialic acid; (ii) a low expression of the cell surface proteins HLA-II, ICAM-1 or LFA-3 that restrict antigen presentation; (iii) lack of secretion of the cytokine IL-1 or other soluble factors that may be required as secondary signals; or (iv) induction of incomplete T-cell activation resulting in the production of growth factor interleukin-2 (IL-2) or the expression of receptors for IL-2 only. These data suggest the involvement of another cell surface interaction in antigen presentation acting besides the interactions known so far.