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B Cells and CD4^–CD8^– T Cells Are Key Regulators of the Severity of Reactivation Histoplasmosis¹

Division of Infectious Diseases, Veterans Affairs Hospital, University of Cincinnati College of Medicine, Cincinnati, OH 45267

The fungus, Histoplasma capsulatum, produces a persistent infection. Reactivation histoplasmosis is largely a result of impaired immunity, but the perturbations associated with escape of the fungus from host defenses remain ill-defined. We analyzed a murine model of reactivation to elucidate the host defects that permit reactivation. C57BL/6 mice were infected intranasally and, 42 days later, they were depleted of CD4⁺ and CD8⁺ cells. Elimination of these cells, but not either alone, produced a persistent infection over several weeks. Neutralization of IFN-, TNF-, or both did not induce reactivation. Endogenous IL-10 exacerbated reactivation. Depletion of T cells in B cell^–/– mice induced a markedly higher burden in organs when compared with wild type. However, the infection remained persistent. Elimination of CD4⁺ cells alone or neutralization of cytokines increased the fungal load. The persistent infection was not dependent on T cells or NK cells. Elimination of Thy-1.2⁺ cells in mice given mAb to CD4 and CD8 transformed reactivation into a progressive, lethal infection in B cell^–/– and wild-type mice, but the tempo of progression was accelerated in the former. The data reveal the complex control by the host to prevent reactivation of this fungus.

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