The human immune response to Cryptococcus neoformans depends on coordinated interaction of antigen presenting cells with a type-1 CD4 T-helper (Th1) cell response. A. The immune response begins with innate defense in the submucosa through alternative complement opsonization of C. neoformans which allows for efficient phagocytosis by neutrophils, macrophages, and dendritic cells [–]. B. Dendritic cells localize the pathogen to the endolysosome through phagocytosis where the organism is degraded, processed, and antigenic peptides presented on surface major histocompatibility complex class-II (MHC-II) to T-cells in lymphatic tissue [, ]. C&D. When T-cells have a matching T-cell receptor for the peptide, appropriate cytokine signals from dendritic cells allow naïve Th0 T-cells to differentiate into effector T-cells []. E. These effector T-cells, are important in the classical activation of macrophages via interferon-gamma (IFN-γ) for fungal clearance. VEGF is secreted by CD4 T-cells after mannoprotein antigen recognition via MHC class II by macrophages resulting in increases in vascular permeability, chemotaxis of additional macrophages and CD4+CD45RO+ memory T-cells. Macrophages require IFN-γ stimulation to up-regulate anti-microbial peptides, reactive oxygen species, and pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), thereby sufficiently killing the phagocytosed, facultative intracellular fungal cells []. In the absence of an effective Th1 T-cell response, humoral immunity via IgG1, IgG2a, and IgG2b directed toward GXM is ineffective alone [, ], and the adaptive arm of the immune system remains paramount to cryptococcal defense. Observation of delayed-type hypersensitivity responses, requirements for cell-mediated immunity, and IFN-γ dependence all support that a Th1 response is essential to cryptococcal immunity [, , ]. In human clinical studies, the IFN-γ (Th1 cytokine) present in the CSF is associated with the rate of fungal culture clearance [, , ].