Marcus Hunter, Luis R Martinez
Cryptococcal meningoencephalitis (CME) remains a leading cause of AIDS-related mortality, and up to one-quarter of persons living with HIV who survive CME develop cryptococcal immune reconstitution inflammatory syndrome (CME-IRIS) after antiretroviral therapy (ART) initiation. CME-IRIS arises when recovering immunity encounters a high residual fungal antigen burden, yet the temporal adaptive immune dynamics that distinguish protective reconstitution from damaging neuroinflammation are not fully defined. This review synthesizes clinical and experimental data to propose a temporal framework centered on CD4+ T cell polarization, regulatory failure, memory T cell quality, and T-B cell coordination. Before ART, many patients exhibit a Th2-skewed, low-inflammatory state with impaired Th1 responses, reduced antifungal IgM production, and deficient Tfh-B cell coordination, collectively favoring persistent Cryptococcus neoformans antigen burden. With ART, IL-7-driven T cell recovery, Th17/Treg imbalance, Th1/Th17-biased memory responses, and chemokine-guided trafficking of CXCR3+CCR5+ effector cells into the central nervous system can convert this antigen-rich milieu into fulminant neuroinflammation. We further discuss emerging mouse models that recapitulate unmasking CME-IRIS, the contrasting immune profile of Cryptococcus gattii-associated IRIS as a comparative model, and developing therapeutic strategies that include targeted immunomodulators, cell-based therapies, and vaccines. Finally, we highlight future directions - particularly single-cell and spatial transcriptomic profiling of blood and CSF - to resolve which adaptive immune populations drive neuroinflammation and to validate predictive biomarkers for CME-IRIS. A temporally informed view of adaptive immunity in CME-IRIS may refine ART timing, guide risk stratification, and identify new adjunctive interventions for cryptococcosis and related IRIS syndromes.