Immunological mechanism behind reactivated cryptococcosis in persistently infected mice following FTY720 treatment

The Cryptococcus neoformans species complex (CNSC), responsible for cryptococcosis, is controlled by Th1-type immunity, in which IFN-γ-activated macrophages form granulomas that contain infection. Nevertheless, CNSC can evade host immunity and, after the primary infection phase, can shift to a latent infection similar to tuberculosis. Reactivation is thought to occur when immune control fails, but the underlying mechanisms remain poorly understood. FTY720, a functional antagonist of sphingosine-1-phosphate receptors, is primarily used in the treatment of multiple sclerosis. However, there have been reports linking its use to instances of cryptococcosis in patients undergoing treatment. To explore this, we established a novel mouse model using CnT-II mice, which express CD4⁺ T cell receptors specific for chitin deacetylase 2 (Cda2), a major T cell antigen of CNSC. Following infection with encapsulated CNSC, mice developed persistent pulmonary fungal burdens (10²-10³ CFU) accompanied by granulomatous responses, modeling latent infection. Upon FTY720 administration, mice exhibited increased pulmonary fungal burdens, disrupted granuloma integrity, and reduced IFN-γ and IL-12 production. FTY720 also markedly decreased CD4⁺ effector memory (Tem) and effector T cells (Teff) in the lungs, with a particularly profound loss of IFN-γ-producing Tem cells. These findings indicate that our model successfully recapitulates latent cryptococcal infection and reactivation, and demonstrate that FTY720 promotes relapse by depleting protective IFN-γ-producing CD4⁺ Tem cells and impairing Th1-mediated immunity. Given the rising use of FTY720, our study highlights its potential risk in patients with subclinical cryptococcosis and underscores the need for preventive strategies to avert disease progression.