Fig. 8: Graphical model illustrating the immune mechanism of host vaccination by C. neoformans (Cn) Δsgl1.

Upon intranasal administration of C. neoformans Δsgl1, the yeast cells travel down the bronchioles into the alveoli (1) encountering resident alveolar macrophages (AM), dendritic cells (DCs), and γδ T cells. Both sterylglucosides (SGs) and the glucuronoxylomannan (GXM)-rich capsule of C. neoformans Δsgl1 can be found on the surface of yeast cells or/and in the extracellular environment. γδ T cells recognize and respond directly to C. neoformans Δsgl1 via a toll-like receptor 2 (TLR2)-directed mechanism (2) producing the host-protective cytokines IFNγ and IL-17A leading to a pro-inflammatory lung cytokine environment with augmented leukocyte recruitment to the lungs (3) including neutrophils and monocytes that mediate early host control by limiting C. neoformans Δsgl1 replication. Antigen-presenting cells (APCs) become activated, phagocytose the yeast, and travel to the lung-draining lymph node to prime naive CD4⁺ or CD8⁺ T cells when CD4⁺ T cells are absent (4). The naive T cells differentiate into protectively polarized IFNγ- and IL-17A-producing T cells and travel to the lungs (5) resulting in the pulmonary clearance of the mutant. While most recruited leukocytes die upon resolution of the inflammatory response, a small percentage of αβ and γδ T cells become host-protective memory T cells (6) that rapidly respond upon a subsequent WT challenge, promptly producing both IFNγ and IL-17A and conferring strong vaccine protection. Graphical illustration created with BioRender.com.