Complex requirements for nascent and memory immunity in pulmonary histoplasmosis

The presence of functional T cells is often required for successful resolut ion of infections with intracellular pathogens, yet the mechanisms by which they contribute to elimination of the invading pathogen in primary and sec ondary immunity are only partly understood. We report that increased mortal ity of naive alpha/beta TCR+ or CD4(+) T cell-depleted mice infected with t he fungus Histoplasma capsulatum is associated with impairment of IFN-gamma production, Upon secondary infection, mice concomitantly depleted of CD4() and CD8(+) cells exhibit decreased survival beyond day 25 of rechallenge, whereas elimination of either T cell subset or B cell deficiency does not result in accelerated mortality compared with controls. Remarkably, despite a decrease of H. capsulatum CFU in lungs of CD4(+) plus CD8(+)-deficient m ice, a progressive increase in spleen CFU is observed. The ability to contr ol fungus growth in lungs is associated with vigorous TNF-alpha, but not IF N-gamma, production by bronchoalveolar lavage cells. In contrast, spleen ce lls from CD4(+) plus CD8(+)-deficient mice are unable to produce TNF-alpha. Thus, the cellular and molecular requirements for protective immunity vary between primary and secondary infection. Furthermore, in secondary histopl asmosis, a sharp contrast can be drawn between lungs and spleens in their r eliance upon T cells to control fungal replication. The opposing activities of these organs can be ascribed in part to differential production of TNF- alpha.