Immunological correlates of protection mediated by a whole organism, <i>Cryptococcus neoformans</i> , vaccine deficient in chitosan

Abstract

The fungus <i>Cryptococcus neoformans</i> is responsible for >100,000 deaths annually, mostly in persons with impaired CD4⁺ T-cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of <i>C. neoformans</i>, designated as <i>cda1∆2∆3∆</i>. When used as a vaccine, <i>cda1∆2∆3∆</i> protects mice against a subsequent challenge with a virulent <i>C. neoformans</i> strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8⁺ T cells were dispensible, protection was lost in mice genetically deficient in CD4⁺ T cells and the cytokines IFNγ, TNFα, or IL-23. A robust influx of cytokine-producing CD4⁺ T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4⁺ T cells following vaccination, suggesting a strategy to protect persons who are at risk of future CD4⁺ T-cell dysfunction.