The concerted action of several cytokines is necessary for resolution of bo
th primary and secondary infection with Histoplasma capsulation. Among the
soluble factors that contribute to tissue sterilization, TNF-alpha stands a
s a central mediator of protective immunity to this fungus. In this study,
we explored the regulation of protective immunity by TNFR1 and -2, In prima
ry pulmonary infection, both TNFR1(-/-) and -2(-/-) mice manifested a high
mortality after infection with H. capsulatum, although TNFR1(-/-) mice were
more susceptible than TNFR2(-/-) mice. Overwhelming infection in the forme
r was associated with a pronounced decrement in the number of inflammatory
cells in the lungs and elevated IFN-gamma and TNF-alpha levels in the lungs
. In contrast, IFN-gamma levels were markedly decreased in TNFR2(-/-) mice,
and treatment with this cytokine restored protective immunity. Lung macrop
hages from both groups or knockout mice released substantial amounts of NO.
Upon secondary. infection, TNFR2(-/-) mice survived rechallenge and cleare
d infection as efficiently as C57BL/6 animals. In contrast, mice given mAb
to TNFR1 succumbed to reexposure, and the high mortality was accompanied by
a significant increase in fungal burden in the lungs. Both IL-4 and IL-10
were elevated in the lungs of these mice. The results demonstrate the pivot
al influence of TNFR1 and -2 in controlling primary infection and highlight
the differences between these receptors for regulation reexposure histopla
smosis.