Activation of the nuclear factor of activated T cells transcription factor (NF-AT) is a key event underlying lymphocyte action. The CAML (calcium-modulator and cyclophilin ligand) protein is a coinducer of NF-AT activation when overexpressed in Jurkat T cells. A member of the tumor necrosis factor receptor superfamily was isolated by Virtue of its affinity for CAML. Cross-linking of this lymphocyte-specific protein, designated TACl (transmembrane activator and CAML-interactor), on the surface of transfected Jurkat cells with TACl-specific antibodies led to activation of the transcription factors NF-AT, AP-1, acid NF kappa B. TACl-induced activation of NF-AT was specifically blocked by a dominant-negative CAML mutant, thus implicating CAML as a signaling intermediate.