Infection with the virulent Mycobacterium avium strain TMC 724 caused progressive infection in C57BL/6 and BALB/c mice, while infection with a less virulent strain (M. avium SE 01) resulted in chronically persistent bacterial loads. Livers of mice infected with TMC 724 were characterized by progressively expanding tumor-like infiltrations of epithelioid macrophages, while SE 01 induced well-developed, compact epithelioid granulomas that remained constant in size and number for at least 4 months. When C57BL/6 mice were depleted of CD4+ T cells by i.p. administration of specific mAb at the time of infection, their capacity to initiate granuloma formation was completely abrogated during the first 4 weeks of infection. Semi-quantitative competitive RT-PCR of liver homogenates obtained 3 weeks after infection revealed that depletion of CD4+ T cells was accompanied by a 25-fold reduced expression of IFN-gamma mRNA and a 5-fold reduced expression of tumor necrosis factor (TNF)-alpha mRNA when compared to control infected mice. Granuloma morphology in response to either TMC 724 or SE 01 was similar in immunodeficient SCID mice to that observed in syngeneic BALB/c mice. However, SCID mice developed granulomas in a delayed fashion and were less efficient in surrounding infected Kupffer cells with an inflammatory infiltration. The delayed kinetics of granuloma initiation in infected SCID mice was paralleled by a lower mRNA expression for IFN-gamma and TNF-alpha compared to that observed in infected BALB/c mice. mAb-mediated neutralization of IFN-gamma in BALB/c mice significantly reduced inflammatory infiltrations and granuloma formation. These data support the conclusion that CD4+ T cells accelerate granuloma formation by enhancing the production of TNF-alpha and IFN-gamma at the site of infection.