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Perforin Is Required for Primary Immunity to Histoplasma capsulatum

Ping Zhou^*, Brenda L. Freidag^*, Charles C. Caldwell and Robert A. Seder^1,*

^* 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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