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 epithelloid 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-quantltatlve 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-γ mRNA and a 5-fold reduced expression of tumor necrosis factor (TNF)-α mRNA when compared to control Infected mice. Granuioma morphology in response to either TMC 724 or SE 01 was similar in immunodeficlent SCID mice to that observed In syngeneic BALB/c mice. However, SCID mice developed granuiomas In a delayed fashion and were less efficient in surrounding Infected Kupffer cells with an inflammatory infiltration. The delayed kinetics of granuioma Initiation In Infected SCID mice was paralleled by a lower mRNA expression for IFN-γ and TNF-α compared to that observed in Infected BALB/c mice. mAb-mediated neutralization of IFN-γ In BALB/c mice significantly reduced inflammatory infiltrations and granuioma formation. These data support the conclusion that CD4+ T cells accelerate granuioma formation by enhancing the production of TNF-α and IFN-γ at the site of infection.