Role of Capsule and Interleukin-6 in Long-Term Immune Control ofCryptococcus neoformansInfection by Specifically Activated Human Peripheral Blood Mononuclear Cells

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Abstract
Cryptococcus neoformansis a frequent cause of meningoencephalitis in immunosuppressed individuals. To better understand the mechanisms of a protective immune response toC. neoformans, a long-term in vitro model of human immune control of cryptococcal infection was developed. Peripheral blood mononuclear cells (PBMC) prestimulated with heat-killedC. neoformanssignificantly restricted the growth ofC. neoformansafter a subsequent live infection compared to that with unstimulated PBMC. Live infection with encapsulatedC. neoformanswas controlled for as long as 10 days, while infection with acapsular organisms could sometimes be eradicated. During immune control, fungal cells were both intracellular and extracellular within aggregates of mononuclear phagocytes and lymphocytes. Optimal immune control depended on the presence of both CD4+and CD8+T cells. Immune control of cryptococcal growth was more effective following prestimulation with acapsular compared with encapsulated organisms. Prestimulation with acapsular organisms was associated with a significant and prolonged increase in interleukin-6 (IL-6) production compared with prestimulation with encapsulatedC. neoformans. Addition of IL-6 and depletion of CD25+T cells prior to prestimulation and infection with encapsulated organisms resulted in reductions in cryptococcal growth that reached borderline statistical significance. Depletion of CD25+T cells significantly reduced cryptococcal growth in wells with unstimulated PBMC. The results demonstrate an association between high levels of IL-6 and resistance to infection and, through suppression of IL-6 release, an additional mechanism whereby the cryptococcal capsule subverts a protective immune response. Further work is required to clarify the mechanism of action of IL-6 in this setting and any interaction with regulatory T cells.