Requirement for CD4(+) T lymphocytes in host resistance against Cryptococcus neoformans in the central nervous system of immunized mice

The importance of cell-mediated immunity (CMI) and CD4(+) T lymphocytes in host resistance against Cryptococcus neoformans is well documented and is e xemplified by the high susceptibility to progressive infection with this pa thogen of AIDS patients with reduced CD4(+) T-cell numbers. Although much h as been learned about the role of CMI in the clearance of C, neoformans fro m the lungs and other internal organs, less is known about the protective m echanisms in the brain, the organ most frequently involved with a fatal out come of cryptococcosis, We hypothesized that host resistance mechanisms aga inst C, neoformans in the central nervous system (CNS) were similar to thos e outside the CNS (i.e., gamma interferon [IFN-gamma], CD4(+) T cells, and others), To test this hypothesis, we used a murine model of cryptococcal me ningitis whereby cryptococci are introduced directly into the CNS. In exper iments where mice were immunized to mount an anticryptococcal CMI response, our results indicate that immunization induced protective mechanisms that could be detected in the CNS by inhibition of the growth of viable yeast ce lls. Flow cytometric analyses of leukocytes in brain and spinal cord homoge nates revealed that T lymphocytes, macrophages, and neutrophils accumulated in C, neoformans-infected brains of immune mice. In vivo depletion of CD4( +) T cells, but not CD8(+) T cells, resulted in significantly reduced leuko cyte accumulation in the brains of immune mice. Furthermore, depletion of C D4(+) T cells or neutralization of IFN-gamma exacerbated CNS infection in i mmune mice, suggesting a critical role for CMI mechanisms in acquired prote ction in the CNS.