T cells require tumor necrosis factor-alpha to provide protective immunity in mice infected with Histoplasma capsulatum.

We examined whether neutralization of tumor necrosis factor (TNF)-alpha after intranasal exposure of mice to Histoplasma capsulatum was necessary for control of primary or secondary infection. All mice given monoclonal antibody to TNF-alpha on the day of infection or on day 3 after infection died. When antibody was administered on day 5 after infection, 60% of mice with primary infection died, whereas none with secondary infection did. Antibody treatment on day 7 after infection produced a transiently higher fungal burden. Because optimal clearance required TNF-alpha after the onset of infection, we hypothesized that it may regulate T cell function. Lung CD3+ cells were the dominant population of TNF-alpha-producing cells (approximately 40%-70%). Neutralization of this cytokine decreased the number of memory T cells but not the number of activated, proliferating, or interferon-gamma-producing cells. T cells from infected, TNF-alpha-neutralized mice failed to protect T cell-deficient mice. The absence of TNF-alpha induces a defect in T cell-mediated protection.