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Clinical Immunology Section, Laboratory of Clinical Investigation, and
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Protective immunity against primary and secondary infection by the
fungus Histoplasma capsulatum (HC) is multifactorial,
requiring cells of the innate and adaptive immune response. Effector
mechanisms that could mediate intracellular killing of HC include
cytokines such as IFN-
and TNF-
and/or direct cytolytic activity
by T and NK cells. In this regard, although previous work has clearly
demonstrated a critical role for IFN- and TNF- in limiting fungal
growth in primary HC infection, less is known regarding the role of
cytolytic mechanisms. The studies reported here first address the role
of perforin in mediating immunity to HC. Remarkably, perforin-deficient
knockout (PfKO) mice were shown to have accelerated mortality and
increased fungal burden following a lethal or sublethal primary
challenge. These data established an essential role for perforin in
primary immunity systemic HC infection. Interestingly, depletion of
CD8+ T cells in PfKO mice caused a further increase in
fungal burden and accelerated mortality, suggesting a
perforin-independent role for CD8+ T cells. Moreover,
adoptive transfer of CD8+ T cells from PfKO mice into
IFN--/- mice caused a reduction in fungal burden
following infectious challenge compared with control
IFN--/- mice. Together, these data suggest that
CD8+ T cells can mediate immunity to HC through both
perforin-dependent and -independent mechanisms.
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