The activation of naive CD4 T cells by antigen is a critical step in the initiation of an immune response; it requires both ligation of the T-cell receptor (TCR) and the delivery of co-stimulatory factors by accessory cells. We have examined the role of syngeneic accessory cells in the response of purified normal CD4 T cells to anti-CD3 antibody as ligand. We show that the ability to deliver co-stimulatory signals is inducible in B cells by microbial products such as bacterial lipopolysaccharide (LPS), mitogenic influenza viruses, and synthetic polyinosinic-polycytidylic acid (poly-I:C) as a mimic of viral infection. LPS stimulation for 16 h allows the co-stimulatory activity of B cells to become resistant to paraformaldehyde fixation. LPS induction of fixation-resistant co-stimulator activity requires new protein synthesis, as it is inhibited by cycloheximide. Using the anti-CD45RB mAb 16A as marker for naive and memory CD4 T cells, we show that B cells activated by LPS and by poly-I:C can provide co-stimulatory signal to both naive and memory CD4 T cells. By contrast, zymosan particles, which are known to activate macrophages in a variety of assays, do not activate B cells to become co-stimulatory, but do induce this activity in macrophages. These data demonstrate that a variety of infectious agents or their constituents can induce accessory cells to become co-stimulatory for CD4 T cells. They are interpreted in light of a proposed role for two classes of recognition in the induction of the immune responses, specific recognition of antigens and non-specific recognition of infectious agents. These data support the contention that the immune system uses this mechanism to discriminate infectious non-self from non-infectious self.