A T cell-independent protective host response against Cryptococcus neoformans expressed at the primary site of infection in the lung

Abstract

T cell-independent host resistance expressed against a primary lung infection with Cryptococcus neoformans was investigated. Following intratracheal inoculation of the yeast, BALB/cBy scid/scid mice or CD4+ plus CD8+ T cell-depleted BALB/cBy mice developed a primary lung infection that remained stable for several weeks before progressing and disseminating to kill the host. By contrast, normal BALB/cBy hosts resolved the infection after 4 to 8 weeks. Thy+ CD4- CD8- cells were found to accumulate in the pulmonary alveoli of infected scid/scid or normal mice. Depletion of these cells caused the infection to progress more rapidly and resulted 4 weeks later in a 30- to 70-fold increase in yeast numbers in the lungs and dissemination to extrapulmonary sites. Cytofluorometric studies revealed that the Thy+ CD4- CD8- cells responsible were negative for the CD3 T cell marker. A small percentage of these Thy+ CD3- cells expressed asialo-Gm1, but treatment with asialo-Gm1 antibody did not have the same infection-enhancing effect as Thy-1 monoclonal antibody treatment. Further experiments revealed that Thy-1 monoclonal antibody treatment had no effect on the establishment of infectious foci in the brain or liver following intravenous inoculation of the yeast. The data point to the existence of an early resistance mechanism for which Thy+ CD3- CD4- CD8- cells are essential. This mechanism of host defense, while insufficient for complete protection, may be capable of delaying the development of cryptococcal meningoencephalitis by restricting the growth of the yeast at primary sites of infection in the lungs, even in immunodeficient mice.