T helper type 1 (Th1) cells perform a critical role in fighting intracellular organisms, and interleukin-12 (IL-12) is known to promote a Thl response. This study was conducted to identify whether an IL-12-independent Th1 reaction is induced by the varicella-zoster virus (VZV) in human beings. It was found that different intracellular microorganisms could induce IFNgamma but not IL-12 production. Induction of IFNgamma production by VZV was associated with IFNalpha production and phosphorylation of both the signal transducer and activator of transcription-1 (STAT-1) and STAT-4 in lymphocytes. In contrast, Bacillus Calmette-Guerin (BCG) induced IL-12 production in association with STAT-4 but not STAT-1 activation. Anti-IFNalpha but not anti-IL-12 antibodies blocked the VZV-induced Th1 polarization. A patient with an IL-12 receptor beta1 chain deficiency showed a normal VZV- but not a normal BCG-induced Th1 reaction, further supporting the concept of an IFNalpha-mediated, IL-12-independent Th1 reaction in response to certain intracellular infections. Identification of the early Th1 polarization induced by IFNalpha versus IL-12 in response to specific viruses may enable the development of better therapeutic strategies tailored to different infections.